| Title: | Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study. |
| Authors: | Melin B, Dahlin AM, Andersson U, Wang Z, Henriksson R, Hallmans G, Bondy ML, Johansen C, Feychting M, Ahlbom A, Kitahara CM, Wang SS, Ruder AM, Carreón T, Butler MA, Inskip PD, Purdue M, Hsing AW, Mechanic L, Gillanders E, Yeager M, Linet M, Chanock SJ, Hartge P, Rajaraman P |
| Journal: | Int J Cancer |
| Date: | 2013 May 15 |
| Branches: | CGR, EBP, IIB, LTG, OEEB, REB |
| PubMed ID: | 23115063 |
| PMC ID: | PMC3586297 |
| Abstract: | Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. |
| Title: | Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome. |
| Authors: | Jamshidi M, Schmidt MK, Dörk T, Garcia-Closas M, Heikkinen T, Cornelissen S, van den Broek AJ, Schürmann P, Meyer A, Park-Simon TW, Figueroa J, Sherman M, Lissowska J, Keong GT, Irwanto A, Laakso M, Hautaniemi S, Aittomäki K, Blomqvist C, Liu J, Nevanlinna H |
| Journal: | Int J Cancer |
| Date: | 2013 May 1 |
| Branches: | HREB |
| PubMed ID: | 23034890 |
| PMC ID: | not available |
| Abstract: | Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients. |
| Title: | Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial. |
| Authors: | Pinsky PF, Zhu C, Skates SJ, Black A, Partridge E, Buys SS, Berg CD |
| Journal: | Int J Cancer |
| Date: | 2013 May 1 |
| Branches: | EBP |
| PubMed ID: | 23065684 |
| PMC ID: | not available |
| Abstract: | Recently, the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial reported no mortality benefit for annual screening with CA-125 and transvaginal ultrasound (TVU). Currently ongoing is the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which utilizes the risk of ovarian cancer algorithm (ROCA), a statistical tool that considers current and past CA125 values to determine ovarian cancer risk. In contrast, PLCO used a single cutoff for CA125, based on current levels alone. We investigated whether having had used ROCA in PLCO could have, under optimal assumptions, resulted in a significant mortality benefit by applying ROCA to PLCO CA125 screening values. A best-case scenario assumed that all cancers showing a positive screen result earlier with ROCA than under the PLCO protocol would have avoided mortality; under a stage-shift scenario, such women were assigned survival equivalent to Stage I/II screen-detected cases. Updated PLCO data show 132 intervention arm ovarian cancer deaths versus 119 in usual care (relative risk, RR = 1.11). Forty-three ovarian cancer cases, 25 fatal, would have been detected earlier with ROCA, with a median (minimum) advance time for fatal cases of 344 (147) days. Best-case and stage-shift scenarios gave 25 and 19 deaths prevented with ROCA, for RRs of 0.90 (95% CI: 0.69-1.17) and 0.95 (95% CI: 0.74-1.23), respectively. Having utilized ROCA in PLCO would not have led to a significant mortality benefit of screening. However, ROCA could still show a significant effect in other screening trials, including UKCTOCS. |
| Title: | Etiologic heterogeneity in endometrial cancer: Evidence from a Gynecologic Oncology Group trial. |
| Authors: | Brinton LA, Felix AS, McMeekin DS, Creasman WT, Sherman ME, Mutch D, Cohn DE, Walker JL, Moore RG, Downs LS, Soslow RA, Zaino R |
| Journal: | Gynecol Oncol |
| Date: | 2013 May |
| Branches: | HREB |
| PubMed ID: | 23485770 |
| PMC ID: | not available |
| Abstract: | OBJECTIVE: Although the epidemiology of typical endometrial carcinomas (grades 1-2 endometrioid or Type I) is well established, less is known regarding higher grade endometrioid or non-endometrioid carcinomas (Type II). Within a large Gynecologic Oncology Group trial (GOG-210), which included central pathology review, we investigated the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologic categories. METHODS: Based on epidemiologic questionnaire data, risk factor associations, expressed as odds ratios (OR) with 95% confidence intervals (CI), were estimated comparing grade 3 endometrioid and Type II cancers (including histologic subtypes) to grades 1-2 endometrioid cancers. RESULTS: Compared with 2244 grades 1-2 endometrioid cancers, women with Type II cancers (321 serous, 141 carcinosarcomas, 77 clear cell, 42 mixed epithelial with serous or clear cell components) were older; more often non-white, multiparous, current smokers; and less often obese. Risk factors for grade 3 endometrioid carcinomas (n=354) were generally similar to those identified for Type II cancers, although patients with grade 3 endometrioid tumors more often had histories of breast cancer without tamoxifen exposure while those with Type II tumors were more frequently treated with tamoxifen. Patients with serous cancers and carcinosarcomas more frequently had breast cancer histories with tamoxifen treatment compared to patients with other tumors. CONCLUSIONS: Risk factors for aggressive endometrial cancers, including grade 3 endometrioid and non-endometrioid tumors, appear to differ from lower grade endometrioid carcinomas. Our findings support etiologic differences between Type I and II endometrial cancers as well as additional heterogeneity within Type II cancers. |
| Title: | Accuracy of ICD-9-CM codes in identifying infections of pneumonia and herpes simplex virus in administrative data. |
| Authors: | Drahos J, Vanwormer JJ, Greenlee RT, Landgren O, Koshiol J |
| Journal: | Ann Epidemiol |
| Date: | 2013 May |
| Branches: | GEB, HREB, IIB |
| PubMed ID: | 23522903 |
| PMC ID: | not available |
| Abstract: | PURPOSE: Clinical epidemiology studies increasingly rely on electronic medical records data. The validity of International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes is crucial as they are often used to identify conditions of interest. We evaluated the use of archived ICD-9-CM codes to identify two representative infection-related conditions, pneumonia and herpes simplex virus (HSV), in a defined health system. METHODS: Records were obtained for a sample of 175 and 179 patients with ICD-9-CM codes for pneumonia and HSV, respectively. An adjudicated case status was assigned for each subject. RESULTS: The presence of a single ICD-9-CM code had a positive predictive value of 88% for pneumonia and 86% for HSV. False positives (noncases) accounted for less than 10% of records evaluated for each condition. CONCLUSIONS: Our study demonstrates that ICD-9-CM codes for pneumonia and HSV were valid markers of a true history of these conditions, suggesting that ICD-9-CM codes can be used to successfully identify infection-related conditions in epidemiologic studies. However, validation studies for individual conditions may help identify condition-specific strategies to improve the performance of diagnostic codes. |
| Title: | Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. |
| Authors: | Faber MT, Kjær SK, Dehlendorff C, Chang-Claude J, Andersen KK, Høgdall E, Webb PM, Jordan SJ, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Rossing MA, Doherty JA, Lurie G, Thompson PJ, Carney ME, Goodman MT, Ness RB, Modugno F, Edwards RP, Bunker CH, Goode EL, Fridley BL, Vierkant RA, Larson MC, Schildkraut J, Cramer DW, Terry KL, Vitonis AF, Bandera EV, Olson SH, King M, Chandran U, Kiemeney LA, Massuger LF, van Altena AM, Vermeulen SH, Brinton L, Wentzensen N, Lissowska J, Yang HP, Moysich KB, Odunsi K, Kasza K, Odunsi-Akanji O, Song H, Pharaoh P, Shah M, Whittemore AS, McGuire V, Sieh W, Sutphen R, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Pearce CL, Wu AH, Pike MC, Risch HA, Jensen A, Ovarian Cancer Association Consortium |
| Journal: | Cancer Causes Control |
| Date: | 2013 May |
| Branches: | HREB, OEEB |
| PubMed ID: | 23456270 |
| PMC ID: | not available |
| Abstract: | PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease. |
| Title: | Plasma Carotenoid- and Retinol-Weighted Multi-SNP Scores and Risk of Breast Cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. |
| Authors: | Hendrickson SJ, Lindström S, Eliassen AH, Rosner BA, Chen C, Barrdahl M, Brinton L, Buring J, Canzian F, Chanock S, Clavel-Chapelon F, Figueroa JD, Gapstur SM, Garcia-Closas M, Gaudet MM, Haiman CA, Hazra A, Henderson B, Hoover R, Hüsing A, Johansson M, Kaaks R, Khaw KT, Kolonel LN, Le Marchand L, Lissowska J, Lund E, McCullough ML, Peplonska B, Riboli E, Sacerdote C, Sánchez MJ, Tjønneland A, Trichopoulos D, van Gils CH, Yeager M, Kraft P, Hunter DJ, Ziegler RG, Willett WC |
| Journal: | Cancer Epidemiol Biomarkers Prev |
| Date: | 2013 Apr 26 |
| Branches: | CGR, EBP, HREB, LTG, OEEB |
| PubMed ID: | 23515144 |
| PMC ID: | not available |
| Abstract: | BACKGROUND: Dietary and circulating carotenoids have been inversely associated with breast cancer risk, but observed associations may be due to confounding. Single-nucleotide polymorphisms (SNPs) in β-carotene 15,15'-monooxygenase 1 (BCMO1), a gene encoding the enzyme involved in the first step of synthesizing vitamin A from dietary carotenoids, have been associated with circulating carotenoid concentrations and may serve as unconfounded surrogates for those biomarkers. We determined associations between variants in BCMO1 and breast cancer risk in a large cohort consortium.METHODS: We used unconditional logistic regression to test four SNPs in BCMO1 for associations with breast cancer risk in 9,226 cases and 10,420 controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also tested weighted multi-SNP scores composed of the two SNPs with strong, confirmed associations with circulating carotenoid concentrations.RESULTS: Neither the individual SNPs nor the weighted multi-SNP scores were associated with breast cancer risk [OR (95% confidence interval) comparing extreme quintiles of weighted multi-SNP scores = 1.04 (0.94-1.16) for β-carotene, 1.08 (0.98-1.20) for α-carotene, 1.04 (0.94-1.16) for β-cryptoxanthin, 0.95 (0.87-1.05) for lutein/zeaxanthin, and 0.92 (0.83-1.02) for retinol]. Furthermore, no associations were observed when stratifying by estrogen receptor status, but power was limited.CONCLUSIONS: Our results do not support an association between SNPs associated with circulating carotenoid concentrations and breast cancer risk.Impact: Future studies will need additional genetic surrogates and/or sample sizes at least three times larger to contribute evidence of a causal link between carotenoids and breast cancer. Cancer Epidemiol Biomarkers Prev; 22(5); 1-10. ©2013 AACR. |
| Title: | Relationship of serum estrogens and estrogen metabolites to postmenopausal breast cancer risk: a nested case-control study. |
| Authors: | Falk RT, Brinton LA, Dorgan JF, Fuhrman BJ, Veenstra TD, Xu X, Gierach GL |
| Journal: | Breast Cancer Res |
| Date: | 2013 Apr 22 |
| Branches: | EBP, HREB |
| PubMed ID: | 23607871 |
| PMC ID: | not available |
| Abstract: | INTRODUCTION: Elevated levels of circulating estrogens are linked to breast cancer risk among postmenopausal women but little is known about the importance of estrogen metabolism. A recently developed liquid chromatography tandem mass spectrometry-based method (LC-MS/MS) measuring a panel of 15 estrogen metabolites (EM) has been evaluated in one study, linking high levels of 2-pathway metabolites relative to the parent estrogens to reduced breast cancer risk. We analyzed this panel of EM in a nested case-control study of postmenopausal breast cancer. METHODS: Between 1977 and 1987, 6915 women provided blood samples to the Columbia Missouri Serum Bank and were followed for incident breast cancer through December 2002. We studied 215 postmenopausal breast cancer cases and 215 matched controls that were postmenopausal and not using exogenous hormones at the time of blood draw. EM were examined individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring), and by ratios of the groupings. Logistic regression models controlling for matching and breast cancer risk factors were used to calculate quartile-specific odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Significant elevated risks were not observed for individual EM, except for quartiles of 16-epiestriol (p trend =0.07). OR for total EM, the parent estrogens estrone and estradiol, and 2-pathway catechol EM (2-hydroxyestrone and 2-hydroxyestradiol) were elevated but trends were not statistically significant. Among 2-pathway metabolites, risks for the highest levels of 2-hydroxyestrone-3-methyl ether, and 2-methoxyestradiol were reduced; ORs for women in the highest vs. lowest quartiles were 0.57 (95% CI=0.33-0.99) and 0.53 (95% CI=0.30-0.96), respectively. Overall, women with higher levels of 2-pathway EM had a reduced risk of breast cancer, which remained after accounting for levels of parent EM, 4-pathway EM, and 16-pathway EM (all trends, p<0.11). CONCLUSIONS: Women with more extensive hydroxylation along the 2-pathway may have a reduced risk of postmenopausal breast cancer. Further studies are needed to clarify the risks for specific EM and complex patterns of estrogen metabolism. This will require aggregation of EM results from several studies. |
| Title: | Risk of precancer determined by HPV genotype combinations in women with minor cytologic abnormalities. |
| Authors: | Gage JC, Schiffman M, Solomon D, Wheeler CM, Gravitt PE, Castle PE, Wentzensen N |
| Journal: | Cancer Epidemiol Biomarkers Prev |
| Date: | 2013 Apr 19 |
| Branches: | CGB, EBP, HREB |
| PubMed ID: | 23603204 |
| PMC ID: | not available |
| Abstract: | BACKGROUND: Studies suggest that testing for individual HPV genotypes can improve risk stratification in women with minor cytological abnormalities. We evaluated genotyping for HPV16, HPV16/18, and HPV16/18/45 in carcinogenic HPV-positive women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. METHODS: For women enrolled in the ASCUS-LSIL Triage Study (ALTS), we calculated the age-stratified (<30 and 30+ years) positivity, and cumulative risk over two years of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) when testing positive or negative for three genotype combinations: HPV16, HPV16/18, and HPV16/18/45. RESULTS: Among women with ASCUS cytology, HPV16 positivity was 17.1% and increased to 22.0% (P<.001) for HPV16/18 and 25.6% (P<.001) for HPV16/18/45. Among women with LSIL cytology, HPV16 positivity was 21.1% and increased to 30.0% (P<.001) for HPV16/18 and 34.0% (P=.017) for HPV16/18/45. Regardless of cytology and age group, the greatest risk difference between test-positives and test-negatives was observed for HPV16 with decreasing risk stratification for HPV16/18 and HPV16/18/45. However, testing negative for any of the three combinations while being positive for another carcinogenic type still implied a 2-year risk of CIN3+ of 7.8% or greater. CONCLUSIONS: Although genotyping for HPV16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytological abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral. Impact: HPV genotyping in HPV-positive women with minor cytological abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted. |
| Title: | An international comparison of male and female breast cancer incidence rates. |
| Authors: | Ly D, Forman D, Ferlay J, Brinton LA, Cook MB |
| Journal: | Int J Cancer |
| Date: | 2013 Apr 15 |
| Branches: | HREB |
| PubMed ID: | 22987302 |
| PMC ID: | PMC3553266 |
| Abstract: | Global international trends in female breast cancer incidence have been described previously but no comparable analysis of male breast cancer incidence rates has been conducted. We obtained male and female case and population data using Cancer Incidence in Five Continents (CI5). We calculated age-adjusted, sex-specific incidence rates and female-to-male incidence rate ratios (FMIRRs) and compared trends of such for the period 1988-2002. This analysis included 8,681 male breast cancer cases and 1.14 million female breast cancer cases. The highest male incidence rate was observed in Israel at 1.24 per 100,000 man-years, and the highest female incidence rate was observed in the United States at 90.7 per 100,000 woman-years. The lowest incidence rates for males (0.16) and females (18.0) were observed in Thailand. In general, male breast cancer incidence trends were variable; a minority of countries displayed evidence for an increase. In contrast, female incidence rates have been increasing in a majority of countries. The Pearson correlation coefficient (r) for male and female breast cancer incidence rates by country during 1988-2002 was 0.69. Male breast cancer rates were generally less than 1 per 100,000 man-years, in contrast to the much higher rates of female breast cancer, providing for an overall FMIRR of 122. The differences in both incidence rates and time trends between males and females may reflect sex differences in underlying risk factors, pathogenesis, and/or overdiagnosis. Conversely, the high correlation between male and female breast cancer incidences may indicate that both sexes share some common risk factors for breast cancer. |
| Title: | Congenital malformations and testicular germ cell tumors. |
| Authors: | Trabert B, Zugna D, Richiardi L, McGlynn KA, Akre O |
| Journal: | Int J Cancer |
| Date: | 2013 Apr 12 |
| Branches: | HREB |
| PubMed ID: | 23580254 |
| PMC ID: | not available |
| Abstract: | Cryptorchidism is one of the few known risk factors for testicular germ cell tumors (TGCT). It has been postulated that other congenital malformations, in particular hypospadias, are also associated with increased risk; however, associations with birth defects have not been extensively studied. Using Swedish population-based registries we evaluated the relationship between birth defects and risk of TGCT. TGCT cases (n=6,593) diagnosed between 15 and 65 years of age were identified from the Swedish Cancer Registry between 1964 and 2008. Five controls per case were randomly selected from the population register and matched on birth year and birth county. Congenital malformations were identified via linkage with the Hospital Discharge Register. Odds ratios (OR) and 95% confidence intervals (CI) for the association between each group of malformations and TGCT were estimated using conditional logistic regression. In addition to the expected association between cryptorchidism and TGCT risk [OR (95% CI): 3.18 (2.50 to 4.04)], hypospadias [2.41 (1.27 to 4.57)], inguinal hernia [1.37 (1.11-1.68)] and other genital malformations [2.19 (1.17 to 4.10)] were associated with an increased risk of TGCT. Mutual adjustment for cryptorchidism, hypospadias, inguinal hernia, and other genital malformations did not appreciably change the associations (ORs: 3.16; 2.25; 1.30; 1.90, respectively). The other (non-genital) malformations evaluated were not associated with TGCT. These data suggest that developmental urogenital abnormalities, specifically cryptorchidism, hypospadias, and inguinal hernia, are associated with an increased risk of TGCT; further supporting the hypothesis that prenatal exposure(s) related to proper genital development are related to this tumor. © 2013 Wiley Periodicals, Inc. |
| Title: | Race and Colon Cancer Survival in an Equal-Access Healthcare System. |
| Authors: | Andaya AA, Enewold L, Zahm SH, Shriver CD, Stojadinovic A, McGlynn KA, Zhu K |
| Journal: | Cancer Epidemiol Biomarkers Prev |
| Date: | 2013 Apr 10 |
| Branches: | HREB, OD |
| PubMed ID: | 23576691 |
| PMC ID: | not available |
| Abstract: | Studies have shown that whites have a higher colorectal cancer survival rate than blacks. However, it is unclear whether racial disparities result from unequal access to medical care or factors other than healthcare access or both. This study assessed whether non-Hispanic Whites (NHWs) and non-Hispanic Blacks (NHBs) differ in colon cancer (CC) survival in an equal-access healthcare system and examined whether racial differences varied by demographic and tumor characteristics. The study included 2,537 Military Health System patients diagnosed with CC between 1998 and 2007. Median follow-up time was 31.4 months. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) for race, overall and stratified by age at diagnosis, sex, and tumor stage. No difference in overall survival (OS) between NHWs and NHBs was observed in general. However, among patients younger than 50 years old, NHBs experienced significantly worse OS than NHWs (HR: 2.27, 95% CI: 1.48-3.49). Further stratification by sex and tumor stage showed that this racial disparity was confined to women (HR: 2.80, 95% CI: 1.30-6.00) and patients with distant stage disease (HR: 2.65, 95% CI: 1.38-5.08) in this age group. When medical care is equally available to NHWs and NHBs, similar overall CC survival was observed; however, evidence of racial differences in survival was apparent for patients younger than 50 years old. This study suggests that factors other than access to care may be related to racial disparities in CC survival among younger, but not older, patients. |
| Title: | TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. |
| Authors: | Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IeM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H |
| Journal: | Proc Natl Acad Sci U S A |
| Date: | 2013 Apr 9 |
| Branches: | CGB, HREB |
| PubMed ID: | 23530248 |
| PMC ID: | not available |
| Abstract: | Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors. |
| Title: | Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers. |
| Authors: | French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, Khan S, Maranian MJ, O'Reilly M, Hillman KM, Betts JA, Carroll T, Bailey PJ, Dicks E, Beesley J, Tyrer J, Maia AT, Beck A, Knoblauch NW, Chen C, Kraft P, Barnes D, González-Neira A, Alonso MR, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Conroy D, Dennis J, Bolla MK, Wang Q, Hopper JL, Southey MC, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Loehberg CR, Ekici AB, Beckmann MW, Peto J, Dos Santos Silva I, Johnson N, Aitken Z, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias Perez JI, Benitez J, Anton-Culver H, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Engel C, Brauch H, Hamann U, Justenhoven C, GENICA Network, Aaltonen K, Heikkilä P, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Sueta A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, kConFab Investigators, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Peeters S, Smeets A, Floris G, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Sardella D, Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Ng CH, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Schoof N, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Balasubramanian SP, Blot W, Signorello LB, Cai Q, Pharoah PD, Healey CS, Shah M, Pooley KA, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Sng JH, Sim X, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, McKay J, Toland AE, Ambrosone CB, Yannoukakos D, Godwin AK, Shen CY, Hsiung CN, Wu PE, Chen ST, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, Dunning AM |
| Journal: | Am J Hum Genet |
| Date: | 2013 Apr 4 |
| Branches: | BB, CGR, HREB, LTG, OEEB |
| PubMed ID: | 23540573 |
| PMC ID: | PMC3617380 |
| Abstract: | Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. |
| Title: | The long and short of telomeres and cancer association studies. |
| Authors: | Savage SA, Gadalla SM, Chanock SJ |
| Journal: | J Natl Cancer Inst |
| Date: | 2013 Apr 3 |
| Branches: | CGB, CGR, LTG |
| PubMed ID: | 23468461 |
| PMC ID: | PMC3614507 |
| Abstract: |
| Title: | Common genetic variants in the 9p21 region and their associations with multiple tumours. |
| Authors: | Gu F, Pfeiffer RM, Bhattacharjee S, Han SS, Taylor PR, Berndt S, Yang H, Sigurdson AJ, Toro J, Mirabello L, Greene MH, Freedman ND, Abnet CC, Dawsey SM, Hu N, Qiao YL, Ding T, Brenner AV, Garcia-Closas M, Hayes R, Brinton LA, Lissowska J, Wentzensen N, Kratz C, Moore LE, Ziegler RG, Chow WH, Savage SA, Burdette L, Yeager M, Chanock SJ, Chatterjee N, Tucker MA, Goldstein AM, Yang XR |
| Journal: | Br J Cancer |
| Date: | 2013 Apr 2 |
| Branches: | BB, CGB, CGR, EBP, GEB, HGP, HREB, LTG, NEB, OD, OEEB, REB |
| PubMed ID: | 23361049 |
| PMC ID: | PMC3619272 |
| Abstract: | Background:The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers.Methods:We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction.Results:Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007).Conclusion:Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis. |
| Title: | Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer. |
| Authors: | Garcia-Closas M, Rothman N, Figueroa JD, Prokunina-Olsson L, Han SS, Baris D, Jacobs EJ, Malats N, De Vivo I, Albanes D, Purdue MP, Sharma S, Fu YP, Kogevinas M, Wang Z, Tang W, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Johnson A, Schwenn M, Karagas MR, Schned A, Andriole G Jr, Grubb R 3rd, Black A, Gapstur SM, Thun M, Diver WR, Weinstein SJ, Virtamo J, Hunter DJ, Caporaso N, Landi MT, Hutchinson A, Burdett L, Jacobs KB, Yeager M, Fraumeni JF Jr, Chanock SJ, Silverman DT, Chatterjee N |
| Journal: | Cancer Res |
| Date: | 2013 Apr 1 |
| Branches: | BB, CGR, EBP, GEB, HREB, LTG, NEB, OD, OEEB |
| PubMed ID: | 23536561 |
| PMC ID: | not available |
| Abstract: | Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 × 10(-4)) and UGT1A6 (P = 8 × 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211-20. ©2012 AACR. |
| Title: | A genome-wide association study of early menopause and the combined impact of identified variants. |
| Authors: | Perry JR, Corre T, Esko T, Chasman DI, Fischer K, Franceschini N, He C, Kutalik Z, Mangino M, Rose LM, Vernon Smith A, Stolk L, Sulem P, Weedon MN, Zhuang WV, Arnold A, Ashworth A, Bergmann S, Buring JE, Burri A, Chen C, Cornelis MC, Couper DJ, Goodarzi MO, Gudnason V, Harris T, Hofman A, Jones M, Kraft P, Launer L, Laven JS, Li G, McKnight B, Masciullo C, Milani L, Orr N, Psaty BM, ReproGen Consortium, Ridker PM, Rivadeneira F, Sala C, Salumets A, Schoemaker M, Traglia M, Waeber G, Chanock SJ, Demerath EW, Garcia M, Hankinson SE, Hu FB, Hunter DJ, Lunetta KL, Metspalu A, Montgomery GW, Murabito JM, Newman AB, Ong KK, Spector TD, Stefansson K, Swerdlow AJ, Thorsteinsdottir U, Van Dam RM, Uitterlinden AG, Visser JA, Vollenweider P, Toniolo D, Murray A |
| Journal: | Hum Mol Genet |
| Date: | 2013 Apr 1 |
| Branches: | CGR, LTG |
| PubMed ID: | 23307926 |
| PMC ID: | PMC3596848 |
| Abstract: | Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking. |
| Title: | Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. |
| Authors: | Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L, Alter BP, Savage SA |
| Journal: | Hum Genet |
| Date: | 2013 Apr |
| Branches: | CGB, CGR |
| PubMed ID: | 23329068 |
| PMC ID: | PMC3600110 |
| Abstract: | Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer predisposition syndrome caused by aberrant telomere biology. The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation. Germline mutations in telomere biology genes account for approximately one-half of known DC families. Using exome sequencing, we identified mutations in RTEL1, a helicase with critical telomeric functions, in two families with HH. In the first family, two siblings with HH and very short telomeres inherited a premature stop codon from their mother who has short telomeres. The proband from the second family has HH and inherited a premature stop codon in RTEL1 from his father and a missense mutation from his mother, who also has short telomeres. In addition, inheritance of only the missense mutation led to very short telomeres in the proband's brother. Targeted sequencing identified a different RTEL1 missense mutation in one additional DC proband who has bone marrow failure and short telomeres. Both missense mutations affect the helicase domain of RTEL1, and three in silico prediction algorithms suggest that they are likely deleterious. The nonsense mutations both cause truncation of the RTEL1 protein, resulting in loss of the PIP box; this may abrogate an important protein-protein interaction. These findings implicate a new telomere biology gene, RTEL1, in the etiology of DC. |
| Title: | Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. |
| Authors: | Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Australian Cancer Study, Australian Ovarian Cancer Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Gene Environment Interaction and Breast Cancer (GENICA), Swedish Breast Cancer Study (SWE-BRCA), Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Epidemiological study of BRCA1 & BRCA2 Mutation Carriers (EMBRACE), Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO), Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, Dunning AM |
| Journal: | Nat Genet |
| Date: | 2013 Apr |
| Branches: | BB, CGB, CGR, GEB, HREB, LTG, OEEB |
| PubMed ID: | 23535731 |
| PMC ID: | not available |
| Abstract: | TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. |
| Title: | In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. |
| Authors: | Brinton LA, Trabert B, Shalev V, Lunenfeld E, Sella T, Chodick G |
| Journal: | Fertil Steril |
| Date: | 2013 Apr |
| Branches: | HREB |
| PubMed ID: | 23375197 |
| PMC ID: | not available |
| Abstract: | OBJECTIVE: To assess long-term cancer risks associated with in vitro fertilization (IVF). DESIGN: Record-linkage study. SETTING: Health maintenance organization in Israel. PATIENT(S): A total of 87,403 women evaluated and/or treated for infertility on or after September 25, 1994, who were followed for cancer development through June 22, 2011: 522 breast, 41 endometrial, 45 ovarian, 311 in situ cervical, and 32 invasive cervical cancers were identified. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hazard ratios (HRs) for specific cancers. RESULT(S): We found no significant relationships of IVF exposures to the risks of breast, endometrial, or ovarian cancers. However, compared with women with no fertility treatment, the HR for ovarian cancer associated with IVF was 1.58 (95% confidence interval [CI] 0.75-3.29), with higher risk among those receiving four or more cycles (HR 1.78, 95% CI 0.76-4.13). There was also a nonsignificantly elevated risk for endometrial cancer among women who received 1-3 IVF cycles (HR 1.94, 95% CI 0.73-5.12), but additional cycles were associated with less risk. In contrast, the risk of in situ cervical cancer was significantly reduced and invasive cervical cancer nonsignificantly reduced among women receiving IVF as well as other fertility treatments. CONCLUSION(S): Our results regarding long-term effects were largely reassuring, but women receiving IVF should continue to be monitored given that the procedures involve potent ovulation stimulators and repeated ovarian punctures. |
| Title: | Epidemiology: Excess cancer in men-a call for an increased research focus. |
| Authors: | Cook MB |
| Journal: | Nat Rev Clin Oncol |
| Date: | 2013 Apr |
| Branches: | HREB |
| PubMed ID: | 23478284 |
| PMC ID: | not available |
| Abstract: |
| Title: | Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women. |
| Authors: | Delahanty RJ, Beeghly-Fadiel A, Long JR, Gao YT, Lu W, Xiang YB, Zheng Y, Ji BT, Wen WQ, Cai QY, Zheng W, Shu XO |
| Journal: | Hum Reprod |
| Date: | 2013 Apr |
| Branches: | GEB, OEEB |
| PubMed ID: | 23406970 |
| PMC ID: | PMC3600840 |
| Abstract: | STUDY QUESTION: Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? SUMMARY ANSWER: Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. PARTICIPANTS AND SETTING: We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. MAIN RESULTS: For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10(-6), binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. STUDY FUNDING/COMPETING INTERESTS: This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare. |
| Title: | Comparative risk of high-grade histopathology diagnosis after a CIN 1 finding in endocervical curettage versus cervical biopsy. |
| Authors: | Gage JC, Duggan MA, Nation JG, Gao S, Castle PE |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | CGB, HREB |
| PubMed ID: | 23343702 |
| PMC ID: | PMC3608705 |
| Abstract: | OBJECTIVE: No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia grade 1 (CIN 1) result when the concurrent cervical biopsy is not high-grade. For women with these pathologic findings, we assessed their short-term risk of high-grade histopathologic diagnosis in the Calgary Health Region where ECC was routinely performed. MATERIALS AND METHODS: We analyzed pathology and colposcopy reports from 1,902 referral colposcopies where both ECC and biopsies were normal or CIN 1. We calculated the short-term risk of CIN 2 or more severe (CIN 2+) detected 12 to 24 months after colposcopy. Pearson χ tests or Fisher exact tests were used to compare risks of a CIN 2+ diagnosis between combinations of test results and strata of risk factors. RESULTS: The short-term risk of CIN 2+ was the same after a CIN 1 biopsy and CIN 1 ECC (4.9% of 1,389 vs 5.0% of 359, respectively, p = .37). Compared with low-grade referral cytology, the risk of CIN 2+ after high-grade cytology was elevated significantly for CIN 1 ECC (13.3% vs 3.3%, p < .01) and nonsignificantly for CIN 1 biopsy (7.1% vs 4.6%, p = .12). CONCLUSIONS: After low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN 1 ECC or biopsy is equivalent, suggesting similar management. A CIN 1 ECC may warrant different management in the context of high-grade referral cytology. |
| Title: | Genome-wide association studies identify four ER negative-specific breast cancer risk loci. |
| Authors: | Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, Orr N, Rhie SK, Riboli E, Feigelson HS, Le Marchand L, Buring JE, Eccles D, Miron P, Fasching PA, Brauch H, Chang-Claude J, Carpenter J, Godwin AK, Nevanlinna H, Giles GG, Cox A, Hopper JL, Bolla MK, Wang Q, Dennis J, Dicks E, Howat WJ, Schoof N, Bojesen SE, Lambrechts D, Broeks A, Andrulis IL, Guénel P, Burwinkel B, Sawyer EJ, Hollestelle A, Fletcher O, Winqvist R, Brenner H, Mannermaa A, Hamann U, Meindl A, Lindblom A, Zheng W, Devillee P, Goldberg MS, Lubinski J, Kristensen V, Swerdlow A, Anton-Culver H, Dörk T, Muir K, Matsuo K, Wu AH, Radice P, Teo SH, Shu XO, Blot W, Kang D, Hartman M, Sangrajrang S, Shen CY, Southey MC, Park DJ, Hammet F, Stone J, Veer LJ, Rutgers EJ, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Peto J, Schrauder MG, Ekici AB, Beckmann MW, Dos Santos Silva I, Johnson N, Warren H, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Truong T, Laurent-Puig P, Kerbrat P, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Müller H, Arndt V, Stegmaier C, Lichtner P, Lochmann M, Justenhoven C, Ko YD, Gene ENvironmental Interaction and breast CAncer (GENICA) Network, Muranen TA, Aittomäki K, Blomqvist C, Greco D, Heikkinen T, Ito H, Iwata H, Yatabe Y, Antonenkova NN, Margolin S, Kataja V, Kosma VM, Hartikainen JM, Balleine R, kConFab Investigators, Tseng CC, Berg DV, Stram DO, Neven P, Dieudonné AS, Leunen K, Rudolph A, Nickels S, Flesch-Janys D, Peterlongo P, Peissel B, Bernard L, Olson JE, Wang X, Stevens K, Severi G, Baglietto L, McLean C, Coetzee GA, Feng Y, Henderson BE, Schumacher F, Bogdanova NV, Labrèche F, Dumont M, Yip CH, Taib NA, Cheng CY, Shrubsole M, Long J, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Knight JA, Glendon G, Mulligan AM, Tollenaar RA, Seynaeve CM, Kriege M, Hooning MJ, van den Ouweland AM, van Deurzen CH, Lu W, Gao YT, Cai H, Balasubramanian SP, Cross SS, Reed MW, Signorello L, Cai Q, Shah M, Miao H, Chan CW, Chia KS, Jakubowska A, Jaworska K, Durda K, Hsiung CN, Wu PE, Yu JC, Ashworth A, Jones M, Tessier DC, González-Neira A, Pita G, Alonso MR, Vincent D, Bacot F, Ambrosone CB, Bandera EV, John EM, Chen GK, Hu JJ, Rodriguez-Gil JL, Bernstein L, Press MF, Ziegler RG, Millikan RM, Deming-Halverson SL, Nyante S, Ingles SA, Waisfisz Q, Tsimiklis H, Makalic E, Schmidt D, Bui M, Gibson L, Müller-Myhsok B, Schmutzler RK, Hein R, Dahmen N, Beckmann L, Aaltonen K, Czene K, Irwanto A, Liu J, Turnbull C, Familial Breast Cancer Study (FBCS), Rahman N, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, stralian Breast Cancer Tissue Bank (ABCTB) Investigators, Olswold C, Slager S, Pilarski R, Ademuyiwa F, Konstantopoulou I, Martin NG, Montgomery GW, Slamon DJ, Rauh C, Lux MP, Jud SM, Bruning T, Weaver J, Sharma P, Pathak H, Tapper W, Gerty S, Durcan L, Trichopoulos D, Tumino R, Peeters PH, Kaaks R, Campa D, Canzian F, Weiderpass E, Johansson M, Khaw KT, Travis R, Clavel-Chapelon F, Kolonel LN, Chen C, Beck A, Hankinson SE, Berg CD, Hoover RN, Lissowska J, Figueroa JD, Chasman DI, Gaudet MM, Diver WR, Willett WC, Hunter DJ, Simard J, Benitez J, Dunning AM, Sherman ME, Chenevix-Trench G, Chanock SJ, Hall P, Pharoah PD, Vachon C, Easton DF, Haiman CA, Kraft P |
| Journal: | Nat Genet |
| Date: | 2013 Apr |
| Branches: | BB, CGR, EBP, HREB, LTG, OEEB |
| PubMed ID: | 23535733 |
| PMC ID: | not available |
| Abstract: | Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. |
| Title: | HGV2012: leveraging next-generation technology and large datasets to advance disease research. |
| Authors: | Gonzaludo N, Zheng HX, Wang J, Chanock SJ, Jin L, Scherer S, Wijmenga C, Kwok PY, Brookes AJ |
| Journal: | Hum Mutat |
| Date: | 2013 Apr |
| Branches: | CGR, LTG |
| PubMed ID: | 23315969 |
| PMC ID: | PMC3606662 |
| Abstract: | The 13th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2012: Shanghai, China, 6th-8th September 2012) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included advancements in next-generation sequencing (NGS) technology, investigation of common and rare diseases, employing NGS in the clinic, utilizing large datasets that leverage biobanks and population-specific cohorts, and exploration of genomic features. |
| Title: | Erythrocyte omega-6 and omega-3 Fatty acids and mammographic breast density. |
| Authors: | Hudson AG, Reeves KW, Modugno F, Wilson JW, Evans RW, Vogel VG, Gierach GL, Simpson J, Weissfeld JL |
| Journal: | Nutr Cancer |
| Date: | 2013 Apr |
| Branches: | HREB |
| PubMed ID: | 23530640 |
| PMC ID: | not available |
| Abstract: | Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman's correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area. |
| Title: | Follow-up testing after colposcopy: five-year risk of CIN 2+ after a colposcopic diagnosis of CIN 1 or less. |
| Authors: | Katki HA, Gage JC, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519308 |
| PMC ID: | PMC3616505 |
| Abstract: | OBJECTIVE: Most women referred for colposcopy are not diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3 to 5 years. An important question is how many subsequent negative Pap results, or negative Pap and human papillomavirus (HPV) cotest results, are needed before returning to an extended retesting interval. METHODS: We estimated 5-year risks of CIN 2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone, and cotesting) for 20,319 women aged 25 years and older screened from 2003 to 2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN 2+ was not initially diagnosed (i.e., "women with CIN 1/negative colposcopy"). RESULTS: Screening results immediately antecedent to CIN 1/negative colposcopy influenced subsequent 5-year CIN 2+ risk: women with an antecedent HPV-positive/atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap had a lower risk (10%) than those with antecedent atypical squamous cells cannot rule out HSIL (ASC-H; 16%, p < .0001) or high-grade squamous intraepithelial lesion or worse (HSIL+; 24%, p < .0001). For women with an antecedent HPV-positive/ASC-US or LSIL, a single negative cotest approximately 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (1.1%) than 2 sequential negative HPV tests (1.8%, p = .3) or 2 sequential negative Pap results (4.0%, p < .0001). For those with an antecedent ASC-H or HSIL+ Pap, 1 negative cotest 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (2.2%) than 1 negative HPV test (4.4%, p = .4) or 1 negative Pap (7.0%, p = .06); insufficient data existed to calculate the risk after sequential negative cotests for women with high-grade antecedent cytology. CONCLUSIONS: Women with a CIN 1/negative colposcopy followed by negative postcolposcopy tests did not achieve sufficiently low CIN 2+ risk to return to 5-year routine screening. For women with antecedent HPV-positive/ASC-US or LSIL, a single negative postcolposcopy cotest reduced their risk to a level consistent with a 3-year return. For women with antecedent ASC-H or HSIL+, no single negative test result sufficed to reduce their risk to a level consistent with a 3-year return. |
| Title: | Benchmarking CIN 3+ risk as the basis for incorporating HPV and Pap cotesting into cervical screening and management guidelines. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519302 |
| PMC ID: | PMC3616419 |
| Abstract: | OBJECTIVE: In 2012, the US Preventive Services Task Force (USPSTF) and a consensus of 25 organizations endorsed concurrent cytology and human papillomavirus (HPV) testing ("cotesting") for cervical cancer screening. Past screening and management guidelines were implicitly based on risks defined by Pap-alone, without consideration of HPV test results. To promote management that is consistent with accepted practice, new guidelines incorporating cotesting should aim to achieve equal management of women at equal risk of cervical intraepithelial neoplasia grade 3 and cancer (CIN 3+). METHODS: We estimated cumulative 5-year risks of CIN 3+ for 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California over 2003 to 2010. We calculated the implicit risk thresholds for Pap-alone and applied them for new management guidance on HPV and Pap cotesting, citing 2 examples: HPV-positive/atypical squamous cells of undetermined significance (ASC-US) and HPV-negative/Pap-negative. We call this guidance process "benchmarking." RESULTS: A low-grade squamous intraepithelial lesion result, for which immediate colposcopy is prescribed, carries a 5-year CIN 3+ risk of 5.2%, suggesting that test results with similar risks should be managed with colposcopy. Similarly, ASC-US (2.6% risk) is managed with a 6- to 12-month follow-up visit and Pap-negative (0.26% risk) is managed with a 3-year follow-up visit. The 5-year CIN 3+ risk for women with HPV-positive/ASC-US was 6.8% (95% confidence interval = 6.2%-7.6%). This is greater than the 5.2% risk implicitly leading to referral to colposcopy, consistent with current management recommendations that HPV-positive/ASC-US should be referred for immediate colposcopy. The 5-year CIN 3+ risk for women with HPV-negative/Pap-negative was 0.08% (95% confidence interval = 0.07%-0.09%), far below the 0.26% implicitly required for a 3-year return and justifying a longer (e.g., 5-year) return. CONCLUSIONS: Using the principle of "equal management of equal risks," benchmarking to implicit risk thresholds based on Pap-alone can be used to achieve safe and consistent incorporation of cotesting. |
| Title: | Five-year risk of CIN 3+ to guide the management of women aged 21 to 24 years. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519307 |
| PMC ID: | PMC3616448 |
| Abstract: | OBJECTIVE: Current US national guidelines recommend beginning screening at age 21 using Pap tests only, with cotesting starting at age 30. To inform the management of Pap test abnormalities among women aged 21 to 24 years, who have extremely low cancer risks, we compared risks of CIN 3+ among women aged 21 to 24 versus 25 to 29 years or 30 to 64 years. METHODS: We estimated 5-year risks of CIN 3+ given different Pap test results, with human papillomavirus (HPV) triage of atypical squamous cells of undetermined significance (ASC-US), among 133,947 women aged 21 to 24 years, compared with 135,382 women aged 25 to 29 years and 965,360 women aged 30 to 64 years, between 2003 and 2010 at Kaiser Permanente Northern California. RESULTS: There were 3 cancers diagnosed during follow-up in women aged 21 to 24 years. After high-grade Pap results (0.6% of Pap results), the 5-year CIN 3+ risks among women aged 21 to 24 years were comparable to those aged 25 to 29 and 30 to 64 years (atypical glandular cells, 6.9% vs 14% vs 8.5%, p = .8; atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion, 16% vs 24% vs 18%, p = .8; high-grade squamous intraepithelial lesion, 28% vs 28% vs 47%, p = .4). After low-grade squamous intraepithelial lesion, the 5-year CIN 3+ risk was lower among women aged 21 to 24 years (3.0%) than that among women aged 25 to 29 years (5.0%, p = .01) or aged 30 to 64 years (5.2%, p = .0002). Although the 5-year CIN 3+ risk after HPV-negative/ASC-US was similar across all 3 groups (0.57% vs 0.59% vs 0.43%, p = 1), risk after HPV-positive/ASC-US was lower among women aged 21 to 24 years (4.4%) than that among women aged 25 to 29 years (7.1%, p < .0001) or 30 to 64 years (6.8%, p < .0001). CONCLUSIONS: Women aged 21 to 24 years had almost zero cancer risk, and positive Pap test results predicted low CIN 3+ risk except for the 0.6% of women with high-grade Pap results. The generally low risk supports conservative management of women aged 21 to 24 years. |
| Title: | Five-year risk of recurrence after treatment of CIN 2, CIN 3, or AIS: performance of HPV and Pap cotesting in posttreatment management. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519309 |
| PMC ID: | PMC3616418 |
| Abstract: | OBJECTIVE: After excisional treatment, cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) can recur. It is not clear how many negative posttreatment Pap or cotest results are needed to ensure adequate safety against CIN 2+ before returning to extended retesting intervals. METHODS: We observed 5-year risks of CIN 2+ for 3 follow-up management strategies after treatment (Pap-alone, human papillomavirus [HPV]-alone, and HPV/Pap cotesting) for 3,273 women aged 25 years and older who were treated for CIN 2, CIN 3, or adenocarcinoma in situ (AIS) between 2003 and 2010 at Kaiser Permanente Northern California. RESULTS: Five-year risks of recurrent CIN 2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN 2 preceded by HPV-positive/atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion to 16% for CIN 3/AIS preceded by atypical glandular cells (AGC)/atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (ASC-H)/high-grade squamous intraepithelial lesion or worse (HSIL+) (p < .0001). However, after posttreatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN 2+ risk after a negative posttreatment cotest (2.4%) was lower than that following a negative HPV test (3.7%, p = .3) or negative Pap result (4.2%, p = .1). Two negative posttreatment tests of each kind conferred slightly lower 5-year CIN 2+ risk than one (2 negative Pap tests vs. 1, 2.7% vs 4.2%, p = .2; 2 negative HPV tests vs. 1, 2.7% vs 3.7%, p = .7; 2 negative cotests vs. 1, 1.5% vs 2.4%, p = .8). The 5-year CIN 2+ risk after 2 negative cotests of 1.5% (95% confidence interval = 0.3%-7.2%) approached the 0.68% risk after a negative Pap test during routine screening. CONCLUSIONS: Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated for CIN 3/AIS had a substantial risk of developing CIN 2+ posttreatment. On the basis of the principle of "equal management of equal risks," after negative test results posttreatment, no subgroup of women achieved risk sufficiently low to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN 2+ than either negative Pap tests or HPV tests alone. |
| Title: | Five-year risks of CIN 2+ and CIN 3+ among women with HPV-positive and HPV-negative LSIL Pap results. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519304 |
| PMC ID: | PMC3637971 |
| Abstract: | OBJECTIVE: Low-grade squamous intraepithelial lesion (LSIL) Pap results do not typically lead to human papillomavirus (HPV) testing. HPV triage is not cost-effective because most cases are HPV-positive. However, under new national guidelines recommending cotesting for women aged 30 to 64 years, clinicians will increasingly receive the HPV test result with LSIL Pap results. Some authors have suggested that HPV triage might be effective at older ages, when the percentage of HPV positivity among women with LSIL declines. METHODS: We estimated 5-year risks of CIN 2+ and CIN 3+ among 9,033 women aged 30 to 64 years who had both an HPV test and an LSIL Pap result. RESULTS: HPV positivity among women with LSIL decreased only slightly with age (30 to 34 vs 60 to 64 years, 88% vs 72%, p < .0001). The 5-year risks of CIN 2+ and CIN 3+ of women aged 30 to 64 years testing HPV-positive/LSIL were larger than those among women testing HPV-negative/LSIL (CIN 2+, 19% vs 5.1%, p < .0001; CIN 3+, 6.1% vs 2.0%, p<.0001). The 5-year risk of CIN 3+ in HPV-negative/LSIL women was similar to that for women with atypical squamous cells of undetermined significance (ASC-US) Pap test result without knowledge of HPV test results (2.0% vs 2.6%, p = .4). CONCLUSIONS: HPV-negative/LSIL posed lower risk than other Pap results that guidelines currently recommend for referral to immediate colposcopy. By the principle of "equal management of equal risks," women with HPV-negative/LSIL might reasonably be managed similarly to those with ASC-US Pap results without knowledge of HPV testing, that is, retesting at 6 to 12 months, rather than immediate colposcopy. Although the HPV test result for LSIL Pap results provides actionable information to clinicians who screen with cotesting, the high HPV positivity of LSIL at even the oldest ages suggests the lack of cost-effectiveness of HPV triage of LSIL for clinicians who do not use routine cotesting. |
| Title: | Five-year risks of CIN 3+ and cervical cancer among women with HPV testing of ASC-US Pap results. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519303 |
| PMC ID: | PMC3616508 |
| Abstract: | OBJECTIVE: New screening guidelines recommend that human papillomavirus (HPV)-negative/atypical squamous cells of undetermined significance (ASC-US) results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented. METHODS: We estimated 5-year risks of cervical intraepithelial neoplasia (CIN) 3+ and of cancer among 2 groups of women between 2003 and 2010 at Kaiser Permanente Northern California: 27,050 aged 30 to 64 years who underwent HPV and Pap cotesting and had an ASC-US Pap result and 12,209 aged 25 to 29 years who underwent HPV triage of ASC-US. RESULTS: Five-year risks of CIN 3+ and of cancer among women aged 30 to 64 years testing HPV-negative/ASC-US and among 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN 3+, 0.43% vs 0.26%, p = .001; cancer, 0.050% vs 0.025%, p = .1). The increased risk of cancer after HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60 to 64 years (0.26% vs 0.035%, p = .3). Five-year risks of CIN 3+ and cancer among women with HPV-negative/ASC-US results were substantially higher than those among women testing HPV-negative/Pap-negative (CIN 3+, 0.43% vs 0.08%, p < .0001; cancer, 0.050% vs 0.011%, p = .003). For women aged 30 to 64 years testing HPV-positive/ASC-US, 5-year risks of CIN 3+ and cancer were slightly higher than those among 9,374 women with low-grade squamous intraepithelial lesion (LSIL) (CIN 3+, 6.8% vs 5.2%, p = .0007; cancer, 0.41% vs 0.16%, p = .04). Similar patterns were seen for women aged 25 to 29 years. CONCLUSIONS: Women with HPV-negative/ASC-US had a similar risk as women testing Pap-negative alone but had a higher risk than women testing HPV-negative/Pap-negative. Based upon the principle of "equal management of equal risks," our findings support the equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60 to 64 years may be higher for women testing HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly. |
| Title: | Five-year risks of CIN 3+ and cervical cancer among women with HPV-positive and HPV-negative high-grade Pap results. |
| Authors: | Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, Cheung LC, Raine-Bennett T, Gage JC, Kinney WK |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519305 |
| PMC ID: | PMC3616447 |
| Abstract: | OBJECTIVE: High-grade Pap results (e.g., atypical glandular cells [AGC], atypical squamous cells cannot rule out HSIL [ASC-H], and high-grade squamous intraepithelial lesion [HSIL]) predict high cancer risks, resulting in referral for colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 years and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context. METHODS: From a cohort of 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks for cervical cancer and CIN 3+ after AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results. RESULTS: HPV positivity of AGC Pap results was 25% and decreased with age (30 to 34 vs 60 to 64 years, 44% vs 17%, p < .0001), whereas HPV positivity of ASC-H and HSIL was much higher (71% and 94%) and decreased less with age. Even for these high-grade Pap results, 5-year CIN 3+ risks differed substantially between HPV-positive and HPV-negative women (AGC, 33% vs 0.93%, p < .0001; ASC-H, 25% vs 3.5%, p < .0001; HSIL, 49% vs 30%, p = .006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC, 9.0% vs 0.37%, p < .0001; ASC-H, 2.5% vs 2.1%, p = .8; HSIL, 6.6% vs 6.8%, p = .7). CONCLUSIONS: The risks of CIN 3+ among women with HPV-negative high-grade Pap results were lower than those among women with HPV-positive high-grade Pap results, especially after AGC. However, by the principle of "equal management of equal risks," all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results. |
| Title: | Aggregate-data estimation of an individual patient data linear random effects meta-analysis with a patient covariate-treatment interaction term. |
| Authors: | Kovalchik SA |
| Journal: | Biostatistics |
| Date: | 2013 Apr |
| Branches: | BB |
| PubMed ID: | 23001065 |
| PMC ID: | PMC3590924 |
| Abstract: | Individual patient-data meta-analysis of randomized controlled trials is the gold standard for investigating how patient factors modify the effectiveness of treatment. Because participant data from primary studies might not be available, reliable alternatives using published data are needed. In this paper, I show that the maximum likelihood estimates of a participant-level linear random effects meta-analysis with a patient covariate-treatment interaction can be determined exactly from aggregate data when the model's variance components are known. I provide an equivalent aggregate-data EM algorithm and supporting software with the R package ipdmeta for the estimation of the "interaction meta-analysis" when the variance components are unknown. The properties of the methodology are assessed with simulation studies. The usefulness of the methods is illustrated with analyses of the effect modification of cholesterol and age on pravastatin in the multicenter placebo-controlled regression growth evaluation statin study. When a participant-level meta-analysis cannot be performed, aggregate-data interaction meta-analysis is a useful alternative for exploring individual-level sources of treatment effect heterogeneity. |
| Title: | 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. |
| Authors: | Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW |
| Journal: | J Low Genit Tract Dis |
| Date: | 2013 Apr |
| Branches: | BB, CGB, HREB |
| PubMed ID: | 23519301 |
| PMC ID: | not available |
| Abstract: | A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up. |
| Title: | Agreement for tumor grade of ovarian carcinoma: analysis of archival tissues from the surveillance, epidemiology, and end results residual tissue repository. |
| Authors: | Matsuno RK, Sherman ME, Visvanathan K, Goodman MT, Hernandez BY, Lynch CF, Ioffe OB, Horio D, Platz C, Altekruse SF, Pfeiffer RM, Anderson WF |
| Journal: | Cancer Causes Control |
| Date: | 2013 Apr |
| Branches: | BB, EBP, HREB |
| PubMed ID: | 23378140 |
| PMC ID: | not available |
| Abstract: | BACKGROUND: Emerging data suggest that ovarian cancers differ by tumor grade. However, the reliability of microscopic grade from paraffin tissue in the general medical community and as reflected in population-based cancer registries is unknown. METHODS: We examined grade agreement between two gynecologic pathologists and the Surveillance Epidemiology and End Results Residual Tissue Repository (SEER). Grade agreement was assessed with percent observer agreement and kappa coefficients for 664 invasive ovarian carcinomas, using previously defined three-tier and two-tier grading systems. A random subset of ovarian carcinomas was selected to compare intra- and inter-pathologist agreement. RESULTS: Five hundred and eighty-six of SEER's 664 tumors were confirmed invasive. Percent agreement was 49 % with fair kappa coefficient = 0.25 (95 % CI: 0.20-0.30) for the 664 tumors. Agreement improved slightly when restricted to the 586 confirmed invasive cancers; it was better for high grade than low grade tumors, for two-tier than three-tier grading systems, and within (66 %) than between study pathologists (43 %). Grade was not a robust independent predictor of ovarian cancer-specific survival. CONCLUSIONS: Grade agreement was fair between SEER and study pathologists irrespective of grading system. Recorded grade in SEER should be used with caution and is probably not a reliable metric for ovarian cancer epidemiology. |
| Title: | Burkitt lymphoma risk in U.S. solid organ transplant recipients. |
| Authors: | Mbulaiteye SM, Clarke CA, Morton LM, Gibson TM, Pawlish K, Weisenburger DD, Lynch CF, Goodman MT, Engels EA |
| Journal: | Am J Hematol |
| Date: | 2013 Apr |
| Branches: | IIB, REB |
| PubMed ID: | 23386365 |
| PMC ID: | PMC3608801 |
| Abstract: | Case reports of Burkitt lymphoma (BL) in transplant recipients suggest that the risk is markedly elevated. Therefore, we investigated the incidence of BL in 203,557 solid organ recipients in the U.S. Transplant Cancer Match Study (1987-2009) and compared it with the general population using standardized incidence ratios. We also assessed associations with demographic and clinical characteristics, and treatments used to induce therapeutic immunosuppression. BL incidence was 10.8 per 100,000 person-years, representing 23-fold (95% confidence interval (CI) 19-28) greater risk than in the general population, and it peaked 3-8 years after the time of transplantation. In adjusted analyses, BL incidence was higher in recipients transplanted when <18 vs. ≥35 years (incidence rate ratio [IRR] 3.49, 95% CI 2.08-5.68) and in those transplanted with a liver (IRR 2.91, 95% CI 1.68-5.09) or heart (IRR 2.39, 95% CI 1.30-4.31) compared with kidney. BL incidence was lower in females than males (IRR 0.45, 95% CI 0.28-0.71), in blacks than whites (IRR 0.33, 95% CI 0.12-0.74), in those with a baseline Epstein-Barr virus (EBV)-seropositive versus EBV-seronegative status (IRR 0.34, 95% CI 0.13-0.93), and in those treated with azathioprine (IRR 0.56, 95% CI 0.34-0.89) or corticosteroids (IRR 0.48, 95% CI 0.29-0.82). Tumors were EBV-positive in 69% of 32 cases with results. EBV positivity was 90% in those aged <18 years and 59% in those aged 18+ years. In conclusion, BL risk is markedly elevated in transplant recipients, and it is associated with certain demographic and clinical features. EBV was positive in most but not all BL cases with results. Am. J. Hematol. 88:245-250, 2013. © 2012 Wiley Periodicals, Inc. |
| Title: | Large-scale genotyping identifies 41 new loci associated with breast cancer risk. |
| Authors: | Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, Wang Q, Dicks E, Lee A, Turnbull C, Rahman N, Breast and Ovarian Cancer Susceptibility Collaboration, Fletcher O, Peto J, Gibson L, Dos Santos Silva I, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Czene K, Irwanto A, Liu J, Waisfisz Q, Meijers-Heijboer H, Adank M, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), van der Luijt RB, Hein R, Dahmen N, Beckman L, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Hopper JL, Southey MC, Makalic E, Schmidt DF, Uitterlinden AG, Hofman A, Hunter DJ, Chanock SJ, Vincent D, Bacot F, Tessier DC, Canisius S, Wessels LF, Haiman CA, Shah M, Luben R, Brown J, Luccarini C, Schoof N, Humphreys K, Li J, Nordestgaard BG, Nielsen SF, Flyger H, Couch FJ, Wang X, Vachon C, Stevens KN, Lambrechts D, Moisse M, Paridaens R, Christiaens MR, Rudolph A, Nickels S, Flesch-Janys D, Johnson N, Aitken Z, Aaltonen K, Heikkinen T, Broeks A, Veer LJ, van der Schoot CE, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Zamora MP, Perez JI, Pita G, Alonso MR, Cox A, Brock IW, Cross SS, Reed MW, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Henderson BE, Schumacher F, Le Marchand L, Andrulis IL, Knight JA, Glendon G, Mulligan AM, kConFab Investigators, stralian Ovarian Cancer Study Group, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, van den Ouweland AM, Jager A, Bui QM, Stone J, Dite GS, Apicella C, Tsimiklis H, Giles GG, Severi G, Baglietto L, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Müller H, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Figueroa J, Lissowska J, Brinton L, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Brüning T, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Radice P, Peterlongo P, Manoukian S, Bonanni B, Devilee P, Tollenaar RA, Seynaeve C, van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Durda K, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Bogdanova NV, Antonenkova NN, Dörk T, Kristensen VN, Anton-Culver H, Slager S, Toland AE, Edge S, Fostira F, Kang D, Yoo KY, Noh DY, Matsuo K, Ito H, Iwata H, Sueta A, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Shu XO, Lu W, Gao YT, Cai H, Teo SH, Yip CH, Phuah SY, Cornes BK, Hartman M, Miao H, Lim WY, Sng JH, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Shen CY, Hsiung CN, Wu PE, Ding SL, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Blot WJ, Signorello LB, Cai Q, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Simard J, Garcia-Closas M, Pharoah PD, Chenevix-Trench G, Dunning AM, Benitez J, Easton DF |
| Journal: | Nat Genet |
| Date: | 2013 Apr |
| Branches: | BB, CGR, HREB, LTG, OEEB |
| PubMed ID: | 23535729 |
| PMC ID: | not available |
| Abstract: | Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. |
| Title: | GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. |
| Authors: | Pharoah PD, Tsai YY, Ramus SJ, Phelan CM, Goode EL, Lawrenson K, Buckley M, Fridley BL, Tyrer JP, Shen H, Weber R, Karevan R, Larson MC, Song H, Tessier DC, Bacot F, Vincent D, Cunningham JM, Dennis J, Dicks E, stralian Cancer Study, stralian Ovarian Cancer Study Group, Aben KK, Anton-Culver H, Antonenkova N, Armasu SM, Baglietto L, Bandera EV, Beckmann MW, Birrer MJ, Bloom G, Bogdanova N, Brenton JD, Brinton LA, Brooks-Wilson A, Brown R, Butzow R, Campbell I, Carney ME, Carvalho RS, Chang-Claude J, Chen YA, Chen Z, Chow WH, Cicek MS, Coetzee G, Cook LS, Cramer DW, Cybulski C, Dansonka-Mieszkowska A, Despierre E, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles D, Edwards R, Ekici AB, Fasching PA, Fenstermacher D, Flanagan J, Gao YT, Garcia-Closas M, Gentry-Maharaj A, Giles G, Gjyshi A, Gore M, Gronwald J, Guo Q, Halle MK, Harter P, Hein A, Heitz F, Hillemanns P, Hoatlin M, Høgdall E, Høgdall CK, Hosono S, Jakubowska A, Jensen A, Kalli KR, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Konecny GE, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee N, Lee J, Leminen A, Lim BK, Lissowska J, Lubiński J, Lundvall L, Lurie G, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, Menon U, Modugno F, Moysich KB, Nakanishi T, Narod SA, Ness RB, Nevanlinna H, Nickels S, Noushmehr H, Odunsi K, Olson S, Orlow I, Paul J, Pejovic T, Pelttari LM, Permuth-Wey J, Pike MC, Poole EM, Qu X, Risch HA, Rodriguez-Rodriguez L, Rossing MA, Rudolph A, Runnebaum I, Rzepecka IK, Salvesen HB, Schwaab I, Severi G, Shen H, Shridhar V, Shu XO, Sieh W, Southey MC, Spellman P, Tajima K, Teo SH, Terry KL, Thompson PJ, Timorek A, Tworoger SS, van Altena AM, van den Berg D, Vergote I, Vierkant RA, Vitonis AF, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wik E, Winterhoff B, Woo YL, Wu AH, Yang HP, Zheng W, Ziogas A, Zulkifli F, Goodman MT, Hall P, Easton DF, Pearce CL, Berchuck A, Chenevix-Trench G, Iversen E, Monteiro AN, Gayther SA, Schildkraut JM, Sellers TA |
| Journal: | Nat Genet |
| Date: | 2013 Apr |
| Branches: | HREB, OEEB |
| PubMed ID: | 23535730 |
| PMC ID: | not available |
| Abstract: | Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer. |
| Title: | Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. |
| Authors: | Puntervoll HE, Yang XR, Vetti HH, Bachmann IM, Avril MF, Benfodda M, Catricalà C, Dalle S, Duval-Modeste AB, Ghiorzo P, Grammatico P, Harland M, Hayward NK, Hu HH, Jouary T, Martin-Denavit T, Ozola A, Palmer JM, Pastorino L, Pjanova D, Soufir N, Steine SJ, Stratigos AJ, Thomas L, Tinat J, Tsao H, Veinalde R, Tucker MA, Bressac-de Paillerets B, Newton-Bishop JA, Goldstein AM, Akslen LA, Molven A |
| Journal: | J Med Genet |
| Date: | 2013 Apr |
| Branches: | GEB, HGP, OD |
| PubMed ID: | 23384855 |
| PMC ID: | PMC3607098 |
| Abstract: | BACKGROUND: CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. METHODS: All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. RESULTS: Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). CONCLUSION: Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation. |
| Title: | Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. |
| Authors: | Schiffman M, Wentzensen N |
| Journal: | Cancer Epidemiol Biomarkers Prev |
| Date: | 2013 Apr |
| Branches: | CGB, HREB |
| PubMed ID: | 23549399 |
| PMC ID: | not available |
| Abstract: | This short review outlines our understanding of cervical cancer precursors, concentrating on the central etiologic role of persistent human papillomavirus infection. The stages of cervical carcinogenesis are better understood than for most other major cancers, providing a successful cancer etiology and prevention model. Cancer Epidemiol Biomarkers Prev; 22(4); 553-60. ©2013 AACR. |
| Title: | A combined p-value test for multiple hypothesis testing |
| Authors: | Zhang SP, Chen HS, Pfeiffer RM |
| Journal: | Journal of Statistical Planning and Inference |
| Date: | 2013 Apr |
| Branches: | BB |
| PubMed ID: | |
| PMC ID: | not available |
| Abstract: | Tests that combine p-values, such as Fisher's product test, are popular to test the global null hypothesis H0 that each of n component null hypotheses, H1,…,Hn, is true versus the alternative that at least one of H1,…,Hn is false, since they are more powerful than classical multiple tests such as the Bonferroni test and the Simes tests. Recent modifications of Fisher's product test, popular in the analysis of large scale genetic studies include the truncated product method (TPM) of , the rank truncated product (RTP) test of and more recently, a permutation based test-the adaptive rank truncated product (ARTP) method of . The TPM and RTP methods require users' specification of a truncation point. The ARTP method improves the performance of the RTP method by optimizing selection of the truncation point over a set of pre-specified candidate points. In this paper we extend the ARTP by proposing to use all the possible truncation points {1,…,n} as the candidate truncation points. Furthermore, we derive the theoretical probability distribution of the test statistic under the global null hypothesis H0. Simulations are conducted to compare the performance of the proposed test with the Bonferroni test, the Simes test, the RTP test, and Fisher's product test. The simulation results show that the proposed test has higher power than the Bonferroni test and the Simes test, as well as the RTP method. It is also significantly more powerful than Fisher's product test when the number of truly false hypotheses is small relative to the total number of hypotheses, and has comparable power to Fisher's product test otherwise. |
| Title: | Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. |
| Authors: | Permuth-Wey J, Lawrenson K, Shen HC, Velkova A, Tyrer JP, Chen Z, Lin HY, Ann Chen Y, Tsai YY, Qu X, Ramus SJ, Karevan R, Lee J, Lee N, Larson MC, Aben KK, Anton-Culver H, Antonenkova N, Antoniou AC, Armasu SM, stralian Cancer Study, stralian Ovarian Cancer Study, Bacot F, Baglietto L, Bandera EV, Barnholtz-Sloan J, Beckmann MW, Birrer MJ, Bloom G, Bogdanova N, Brinton LA, Brooks-Wilson A, Brown R, Butzow R, Cai Q, Campbell I, Chang-Claude J, Chanock S, Chenevix-Trench G, Cheng JQ, Cicek MS, Coetzee GA, Consortium of Investigators of Modifiers of BRCA1/2, Cook LS, Couch FJ, Cramer DW, Cunningham JM, Dansonka-Mieszkowska A, Despierre E, Doherty JA, Dörk T, du Bois A, Dürst M, Easton DF, Eccles D, Edwards R, Ekici AB, Fasching PA, Fenstermacher DA, Flanagan JM, Garcia-Closas M, Gentry-Maharaj A, Giles GG, Glasspool RM, Gonzalez-Bosquet J, Goodman MT, Gore M, Górski B, Gronwald J, Hall P, Halle MK, Harter P, Heitz F, Hillemanns P, Hoatlin M, Høgdall CK, Høgdall E, Hosono S, Jakubowska A, Jensen A, Jim H, Kalli KR, Karlan BY, Kaye SB, Kelemen LE, Kiemeney LA, Kikkawa F, Konecny GE, Krakstad C, Krüger Kjaer S, Kupryjanczyk J, Lambrechts D, Lambrechts S, Lancaster JM, Le ND, Leminen A, Levine DA, Liang D, Kiong Lim B, Lin J, Lissowska J, Lu KH, Lubiński J, Lurie G, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, Menon U, Modugno F, Moysich KB, Nakanishi T, Narod SA, Nedergaard L, Ness RB, Nevanlinna H, Nickels S, Noushmehr H, Odunsi K, Olson SH, Orlow I, Paul J, Pearce CL, Pejovic T, Pelttari LM, Pike MC, Poole EM, Raska P, Renner SP, Risch HA, Rodriguez-Rodriguez L, Anne Rossing M, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schwaab I, Severi G, Shridhar V, Shu XO, Shvetsov YB, Sieh W, Song H, Southey MC, Spiewankiewicz B, Stram D, Sutphen R, Teo SH, Terry KL, Tessier DC, Thompson PJ, Tworoger SS, van Altena AM, Vergote I, Vierkant RA, Vincent D, Vitonis AF, Wang-Gohrke S, Palmieri Weber R, Wentzensen N, Whittemore AS, Wik E, Wilkens LR, Winterhoff B, Ling Woo Y, Wu AH, Xiang YB, Yang HP, Zheng W, Ziogas A, Zulkifli F, Phelan CM, Iversen E, Schildkraut JM, Berchuck A, Fridley BL, Goode EL, Pharoah PD, Monteiro AN, Sellers TA, Gayther SA |
| Journal: | Nat Commun |
| Date: | 2013 Mar 27 |
| Branches: | CGR, HREB, LTG, OEEB |
| PubMed ID: | 23535648 |
| PMC ID: | not available |
| Abstract: | Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. |
| Title: | Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23. |
| Authors: | Schumacher FR, Wang Z, Skotheim RI, Koster R, Chung CC, Hildebrandt MA, Kratz CP, Bakken AC, Timothy Bishop D, Cook MB, Erickson RL, Fosså SD, Greene MH, Jacobs KB, Kanetsky PA, Kolonel LN, Loud JT, Korde LA, Le Marchand L, Pablo Lewinger J, Lothe RA, Pike MC, Rahman N, Rubertone MV, Schwartz SM, Siegmund KD, Skinner EC, Turnbull C, Van Den Berg DJ, Wu X, Yeager M, Nathanson KL, Chanock SJ, Cortessis VK, McGlynn KA |
| Journal: | Hum Mol Genet |
| Date: | 2013 Mar 22 |
| Branches: | CGB, CGR, HREB, LTG |
| PubMed ID: | 23462292 |
| PMC ID: | not available |
| Abstract: | Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk. |
| Title: | Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins. |
| Authors: | Cozen W, Yu G, Gail MH, Ridaura VK, Nathwani BN, Hwang AE, Hamilton AS, Mack TM, Gordon JI, Goedert JJ |
| Journal: | Br J Cancer |
| Date: | 2013 Mar 19 |
| Branches: | BB, GEB, IIB |
| PubMed ID: | 23443674 |
| PMC ID: | PMC3619077 |
| Abstract: | BACKGROUND: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. METHODS: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. RESULTS: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs. CONCLUSION: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment. |
| Title: | Analysis of Over 10,000 Cases Finds No Association between Previously-Reported Candidate Polymorphisms and Ovarian Cancer Outcome. |
| Authors: | White KL, Vierkant RA, Fogarty Z, Charbonneau B, Block MS, Pharoah PD, Chenevix-Trench G, Rossing MA, Cramer DW, Pearce L, Schildkraut JM, Menon U, Kruger Kjær S, Levine DA, Gronwald J, Anton-Culver H, Whittemore AS, Karlan BY, Lambrechts D, Wentzensen N, Kupryjanczyk J, Chang-Claude J, Bandera EV, Hogdall EV, Heitz F, Kaye S, Fasching PA, Campbell IG, Goodman MT, Pejovic T, Bean YT, Lurie G, Eccles D, Hein A, Beckmann MW, Ekici AB, Paul J, Brown R, Flanagan JM, Harter P, du Bois A, Schwaab I, Hogdall CK, Lundvall L, Olson SH, Orlow I, Paddock LE, Rudolph A, Eilber U, Dansonka-Mieszkowska A, Rzepecka IK, Ziolkowska-Seta I, Brinton LA, Yang HP, Garcia-Closas M, Despierre E, Lambrechts S, Vergote I, Walsh C, Lester J, Sieh W, McGuire V, Rothstein JH, Ziogas A, Lubinski J, Cybulski C, Menkiszak J, Jensen A, Gayther SA, Ramus SJ, Gentry-Maharaj A, Berchuck A, Wu AH, Pike MC, Van Den Berg D, Terry KL, Vitonis AF, Doherty JA, Johnatty SE, Defazio A, Song H, Tyrer J, Sellers TA, Phelan CM, Kalli KR, Cunningham JM, Fridley BL, Goode EL |
| Journal: | Cancer Epidemiol Biomarkers Prev |
| Date: | 2013 Mar 19 |
| Branches: | HREB |
| PubMed ID: | 23513043 |
| PMC ID: | not available |
| Abstract: | BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. |
| Title: | Index-based dietary patterns and the risk of prostate cancer in the NIH-AARP diet and health study. |
| Authors: | Bosire C, Stampfer MJ, Subar AF, Park Y, Kirkpatrick SI, Chiuve SE, Hollenbeck AR, Reedy J |
| Journal: | Am J Epidemiol |
| Date: | 2013 Mar 15 |
| Branches: | NEB |
| PubMed ID: | 23408548 |
| PMC ID: | not available |
| Abstract: | Few studies have investigated the relationship between overall diet and the risk of prostate cancer. We examined the association between 3 diet quality indices-the Healthy Eating Index-2005 (HEI-2005), Alternate Healthy Eating Index-2010 (AHEI-2010), and alternate Mediterranean diet score (aMED)-and prostate cancer risk. At baseline, dietary intake was assessed in a cohort of 293,464 US men in the National Institutes of Health (NIH)-AARP Diet and Health Study. Cox proportional hazards regression was used to estimate hazard ratios. Between 1995 and 2006, we ascertained 23,453 incident cases of prostate cancer, including 2,251 advanced cases and 428 fatal cases. Among men who reported a history of prostate-specific antigen testing, high HEI-2005 and AHEI-2010 scores were associated with lower risk of total prostate cancer (for the highest quintile compared with the lowest, hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.86, 0.98, P for trend = 0.01; and HR = 0.93, 95% CI: 0.88, 0.99, P for trend = 0.05, respectively). No significant association was observed between aMED score and total prostate cancer or between any of the indices and advanced or fatal prostate cancer, regardless of prostate-specific antigen testing status. In individual component analyses, the fish component of aMED and ω-3 fatty acids component of AHEI-2010 were inversely associated with fatal prostate cancer (HR = 0.79, 95% CI: 0.65, 0.96, and HR = 0.94, 95% CI: 0.90, 0.98, respectively). |
| Title: | Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. |
| Authors: | Mirabello L, Schiffman M, Ghosh A, Rodriguez AC, Vasiljevic N, Wentzensen N, Herrero R, Hildesheim A, Wacholder S, Scibior-Bentkowska D, Burk RD, Lorincz AT |
| Journal: | Int J Cancer |
| Date: | 2013 Mar 15 |
| Branches: | BB, CGB, HREB, IIB |
| PubMed ID: | 22847263 |
| PMC ID: | PMC3493709 |
| Abstract: | We explored the association of human papillomavirus type 16 (HPV16) DNA methylation with age, viral load, viral persistence and risk of incident and prevalent high grade CIN (CIN2+) in serially collected specimens from the Guanacaste, Costa Rica cohort. 273 exfoliated cervical cell specimens (diagnostic and pre-diagnostic) were selected: (1) 92 with HPV16 DNA clearance (controls), (2) 72 with HPV16 DNA persistence (without CIN2+) and (3) 109 with CIN2+. DNA was extracted, bisulfite converted and methylation was quantified using pyrosequencing assays at 66 CpGs across the HPV genome. The Kruskal-Wallis test was used to determine significant differences among groups, and receiver operating characteristic curve analyses were used to evaluate how well methylation identified women with CIN2+. In diagnostic specimens, 88% of CpG sites had significantly higher methylation levels in CIN2+ after correction for multiple tests compared with controls. The highest area under the ROC curve (AUC) was 0.82 for CpG site 6457 in L1, and a diagnostic sensitivity of 91% corresponded to a specificity of 60% for CIN2+. Prospectively, 17% of CpG sites had significantly higher methylation in pre-diagnostic CIN2+ specimens (median time of 3 years before diagnosis) versus controls. The strongest pre-diagnostic CpG site was 6367 in L1 with an AUC of 0.76. Age-stratified analyses suggested that women older than the median age of 28 years have an increased risk of precancer associated with high methylation. Higher methylation in CIN2+ cases was not explained by higher viral load. We conclude that elevated levels of HPV16 DNA methylation may be useful to predict concurrently diagnosed as well as future CIN2+. |
| Title: | Computational lymphatic node models in pediatric and adult hybrid phantoms for radiation dosimetry. |
| Authors: | Lee C, Lamart S, Moroz BE |
| Journal: | Phys Med Biol |
| Date: | 2013 Mar 7 |
| Branches: | REB |
| PubMed ID: | 23391692 |
| PMC ID: | not available |
| Abstract: | We developed models of lymphatic nodes for six pediatric and two adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right) and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in six lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for smaller phantoms due to the shorter inter-organ distances compared to the bigger phantoms. By testing sensitivity of S values to random sampling and voxel resolution, we confirmed that the lymph node model is reasonably stable and consistent for different random samplings and voxel resolutions. |