Publications Search - Abstract View

Title: Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case-control study.
Authors: Trabert B,  Troisi R,  Grotmol T,  Ekbom A,  Engeland A,  Gissler M,  Glimelius I,  Madanat-Harjuoja L,  Sørensen HT,  Tretli S,  Gulbech Ording A,  Bjørge T
Journal: Int J Cancer
Date: 2020 Mar 15
Branches: EBP, MEB
PubMed ID: 31173648
PMC ID: PMC6898733
Abstract: Many pregnancy-related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy-related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy-related factors, pregnancy complications and birth characteristics. Utilizing population-based register data from four Nordic countries, we conducted a nested case-control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy-related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39-2.55]; gestational hypertension 1.47 [1.33-1.63]; preeclampsia 1.43 [1.30-1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59-0.69]) and shorter time since last birth (<10 vs. ≥30 years: 0.34 [0.29-0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy-related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.
Title: Prediagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three prospective cohorts in China and Singapore.
Authors: Bassig BA,  Shu XO,  Sjödin A,  Koh WP,  Gao YT,  Adams-Haduch J,  Davis M,  Wang R,  Xiang YB,  Engel LS,  Purdue MP,  Ji BT,  Yang G,  Jones RS,  Langseth H,  Hosgood HD,  Grimsrud TK,  Seow WJ,  Wong JYY,  Hu W,  Chen D,  Zheng W,  Yuan JM,  Lan Q,  Rothman N
Journal: Int J Cancer
Date: 2020 Feb 1
Branches: OEEB
PubMed ID: 31001807
PMC ID: not available
Abstract: Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and β-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between β-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.
Title: The influence of birth cohort and calendar period on global trends in ovarian cancer incidence.
Authors: Cabasag CJ,  Arnold M,  Butler J,  Inoue M,  Trabert B,  Webb PM,  Bray F,  Soerjomataram I
Journal: Int J Cancer
Date: 2020 Feb 1
Branches: MEB
PubMed ID: 30968402
PMC ID: PMC6786921
Abstract: Ovarian cancer is the eighth most common cancer in women worldwide and incidence rates vary markedly by world region. Our study provides a comprehensive overview of ovarian cancer incidence trends globally, examining the influence of birth cohort and period of diagnosis on changing risk. We presented current patterns and trends of ovarian cancer incidence until 2012 using data from successive volumes of Cancer Incidence in Five Contents. The incidence of ovarian cancer is highest in northern and eastern European countries and in northern America. Declining trends were observed in most countries with the exception of a few central and eastern Asian countries. Marked declines were seen in Europe and North America for women aged 50-74 where rates have declined up to 2.4% (95% CI: -3.9, -0.9) annually in Denmark (DNK) over the last decade. Additionally, declines in the incidence rate ratio (IRR) were observed for generations born after the 1930s, with an additional strong period effect seen around 2000 in United States and DNK. In contrast, IRRs increased among younger generations born after the 1950s in Japan and Belarus. Overall, the favorable trends in ovarian cancer incidence is likely due to the increase use of oral contraceptive pills, and changes in the prevalence of other reproductive risk and protective factors for ovarian cancer over the years studied. Changes in disease classifications and cancer registry practices may also partially contribute to the variation in ovarian cancer incidence rates. Thus, continuous cancer surveillance is essential to detect the shifting patterns of ovarian cancer.
Title: Thyroid Dose Estimates for a Cohort of Belarusian Persons Exposed in Utero and During Early Life to Chernobyl Fallout.
Authors: Drozdovitch V,  Minenko V,  Kukhta T,  Trofimik S,  Grakovitch R,  Hatch M,  Cahoon EK,  Veyalkin I,  Polyanskaya O,  Yauseyenka V,  Ostroumova E,  Mabuchi K,  Rozhko A
Journal: Health Phys
Date: 2020 Feb
Branches: REB
PubMed ID: 31869316
PMC ID: PMC6931907
Abstract: Thyroid radiation doses were estimated for a cohort of 2,965 Belarusian persons who were exposed in utero and during early life to fallout from the Chernobyl nuclear power plant accident. Prenatal and postnatal doses to the thyroid due to intake of I, external irradiation from radionuclides deposited on the ground, and ingestion of cesium isotopes (Cs and Cs) were calculated for all cohort members. Dose estimation was based on personal interviews with subjects' mothers; the interviews collected data on subjects' residential history, consumption by mothers during time of pregnancy and breast-feeding, as well as consumption by subjects after birth. Direct instrumental measurements of radioactivity in mothers and the study subjects, if available, were also used for calculation of doses. Intake of I by mothers was found to be the predominant pathway for thyroid exposure for the study subjects. The average thyroid dose due to all exposure pathways was estimated to be 137 mGy (median dose of 25 mGy, maximal dose of 14.8 Gy), including 130 mGy (median dose of 17 mGy, maximal dose of 14.8 Gy) from I intake, 4.9 mGy (median dose of 3.0 mGy, maximal dose of 102 mGy) due to external irradiation, and 2.5 mGy (median dose of 1.7 mGy, maximal dose of 47 mGy) due to ingestion of Cs. The dose estimates will be used to evaluate the radiation-related risk of thyroid cancer and other thyroid diseases in this unique cohort.
Title: Trends in Estimated Thyroid, Salivary Gland, Brain, and Eye Lens Doses From Intraoral Dental Radiography Over Seven Decades (1940 TO 2009).
Authors: Fontana RC,  Pasqual E,  Miller DL,  Simon SL,  Cardis E,  Thierry-Chef I
Journal: Health Phys
Date: 2020 Feb
Branches: EBP
PubMed ID: 31634260
PMC ID: not available
Abstract: The purpose of this study is to support retrospective dose estimation for epidemiological studies by providing estimates of historical absorbed organ doses to the brain, lens of the eye, salivary glands, and thyroid from intraoral dental radiographic examinations performed from 1940 to 2009. We simulated organ doses to an adult over 10 y time periods from 1940 to 2009, based on commonly used sets of x-ray machine settings collected from the literature. Simulations to estimate organ dose were performed using personal computer x-ray Monte Carlo software. Overall, organ doses were less than 1 mGy for a single intraoral radiograph for all decades. From 1940 to 2009, doses to the brain, eye lens, salivary glands, and thyroid decreased by 86, 96, 95, and 89%, respectively. Of these four organs, the salivary glands received the highest doses, with values decreasing from about 0.23 mGy in the 1940s to 0.025 mGy in the 2000s for a single intraoral radiograph. Based on simulations using collected historical data on x-ray technical parameters, improvements in technology and optimization of the technical settings used to perform intraoral dental radiography have resulted in a decrease in absorbed dose to the brain, eye lens, salivary glands, and thyroid over the period from 1940 to 2009.
Title: Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.
Authors: Koutros S,  Kogevinas M,  Friesen MC,  Stewart PA,  Baris D,  Karagas MR,  Schwenn M,  Johnson A,  Monawar Hosain GM,  Serra C,  Tardon A,  Carrato A,  Garcia-Closas R,  Moore LE,  Nickerson ML,  Hewitt SM,  Lenz P,  Schned AR,  Lloreta J,  Allory Y,  Zhang H,  Chatterjee N,  Garcia-Closas M,  Rothman N,  Malats N,  Silverman DT
Journal: Environ Int
Date: 2020 Feb
Branches: EBP, ITEB, LTG, OD, OEEB
PubMed ID: 31864026
PMC ID: not available
Abstract: BACKGROUND: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence). OBJECTIVE: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes. METHODS: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors. RESULTS: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 μg/m3-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 μg/m3-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019). CONCLUSIONS: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.
Title: Absolute risks of cervical precancer among women who fulfill exiting guidelines based on HPV and cytology cotesting.
Authors: Landy R,  Schiffman M,  Sasieni PD,  Cheung LC,  Katki HA,  Rydzak G,  Wentzensen N,  Poitras NE,  Lorey T,  Kinney WK,  Castle PE
Journal: Int J Cancer
Date: 2020 Feb 1
Branches: BB, CGB
PubMed ID: 30861114
PMC ID: PMC6742586
Abstract: US guidelines recommend that most women older than 65 years cease cervical screening after two consecutive negative cotests (concurrent HPV and cytology tests) in the previous 10 years, with one in the last 5 years. However, this recommendation was based on expert opinion and modeling rather than empirical data on cancer risk. We therefore estimated the 5-year risks of cervical precancer (cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ [CIN3]) after one, two and three negative cotests among 346,760 women aged 55-64 years undergoing routine cotesting at Kaiser Permanente Northern California (2003-2015). Women with a history of excisional treatment or CIN2+ were excluded. No woman with one or more negative cotests was diagnosed with cancer during follow-up. Five-year risks of CIN3 after one, two, and three consecutive negative cotests were 0.034% (95% CI: 0.023%-0.046%), 0.041% (95% CI: 0.007%-0.076%) and 0.016% (95% CI: 0.000%-0.052%), respectively (ptrend < 0.001). These risks did not appreciably differ by a positive cotest result prior to the one, two or three negative cotest(s). Since CIN3 risks after one or more negative cotests were significantly below a proposed 0.12% CIN3+ risk threshold for a 5-year screening interval, a longer screening interval in these women is justified. However, the choice of how many negative cotests provide sufficient safety against invasive cancer over a woman's remaining life represents a value judgment based on the harms versus benefits of continued screening. Ideally, this guideline should be informed by longer-term follow-up given that exiting is a long-term decision.
Title: Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.
Authors: McNabb S,  Harrison TA,  Albanes D,  Berndt SI,  Brenner H,  Caan BJ,  Campbell PT,  Cao Y,  Chang-Claude J,  Chan A,  Chen Z,  English DR,  Giles GG,  Giovannucci EL,  Goodman PJ,  Hayes RB,  Hoffmeister M,  Jacobs EJ,  Joshi AD,  Larsson SC,  Le Marchand L,  Li L,  Lin Y,  Männistö S,  Milne RL,  Nan H,  Newton CC,  Ogino S,  Parfrey PS,  Petersen PS,  Potter JD,  Schoen RE,  Slattery ML,  Su YR,  Tangen CM,  Tucker TC,  Weinstein SJ,  White E,  Wolk A,  Woods MO,  Phipps AI,  Peters U
Journal: Int J Cancer
Date: 2020 Feb 1
Branches: MEB, OEEB
PubMed ID: 31037736
PMC ID: PMC6819207
Abstract: Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
Title: Mortality in a cohort of US firefighters from San Francisco, Chicago and Philadelphia: an update.
Authors: Pinkerton L,  Bertke SJ,  Yiin J,  Dahm M,  Kubale T,  Hales T,  Purdue M,  Beaumont JJ,  Daniels R
Journal: Occup Environ Med
Date: 2020 Feb
Branches: OEEB
PubMed ID: 31896615
PMC ID: not available
Abstract: OBJECTIVES: To update the mortality experience of a previously studied cohort of 29 992 US urban career firefighters compared with the US general population and examine exposure-response relationships within the cohort. METHODS: Vital status was updated through 2016 adding 7 years of follow-up. Cohort mortality compared with the US population was evaluated via life table analyses. Full risk-sets, matched on attained age, race, birthdate and fire department were created and analysed using the Cox proportional hazards regression to examine exposure-response associations between select mortality outcomes and exposure surrogates (exposed-days, fire-runs and fire-hours). Models were adjusted for a potential bias from healthy worker survivor effects by including a categorical variable for employment duration. RESULTS: Compared with the US population, mortality from all cancers, mesothelioma, non-Hodgkin's lymphoma (NHL) and cancers of the oesophagus, intestine, rectum, lung and kidney were modestly elevated. Positive exposure-response relationships were observed for deaths from lung cancer, leukaemia and chronic obstructive pulmonary disease (COPD). CONCLUSIONS: This update confirms previous findings of excess mortality from all cancers and several site-specific cancers as well as positive exposure-response relations for lung cancer and leukaemia. New findings include excess NHL mortality compared with the general population and a positive exposure-response relationship for COPD. However, there was no evidence of an association between any quantitative exposure measure and NHL.
Title: Metabolomics and breast cancer: scaling up for robust results.
Authors: Moore SC
Journal: BMC Med
Date: 2020 Jan 31
Branches: MEB
PubMed ID: 32000763
PMC ID: not available
Abstract:
Title: Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035.
Authors: Arnold M,  Park JY,  Camargo MC,  Lunet N,  Forman D,  Soerjomataram I
Journal: Gut
Date: 2020 Jan 30
Branches: MEB
PubMed ID: 32001553
PMC ID: not available
Abstract: OBJECTIVES: The incidence of gastric cancer continues to decrease globally, approaching levels that in some populations could define it as a rare disease. To explore this on a wider scale, we predict its future burden in 34 countries with long-standing population-based data. METHODS: Data on gastric cancer incidence by year of diagnosis, sex and age were extracted for 92 cancer registries in 34 countries included in Cancer Incidence in Five Continents Plus. Numbers of new cases and age-standardised incidence rates (ASR per 100 000) were predicted up to 2035 by fitting and extrapolating age-period-cohort models. RESULTS: Overall gastric cancer incidence rates are predicted to continue falling in the future in the majority of countries, including high-incidence countries such as Japan (ASR 36 in 2010 vs ASR 30 in 2035) but also low-incidence countries such as Australia (ASR 5.1 in 2010 vs ASR 4.6 in 2035). A total of 16 countries are predicted to fall below the rare disease threshold (defined as 6 per 100 000 person-years) by 2035, while the number of newly diagnosed cases remains high and is predicted to continue growing. In contrast, incidence increases were seen in younger age groups (below age 50 years) in both low-incidence and high-incidence populations. CONCLUSIONS: While gastric cancer is predicted to become a rare disease in a growing number of countries, incidence levels remain high in some regions, and increasing risks have been observed in younger generations. The predicted growing number of new cases highlights that gastric cancer remains a major challenge to public health on a global scale.
Title: Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis.
Authors: Papadimitriou N,  Dimou N,  Tsilidis KK,  Banbury B,  Martin RM,  Lewis SJ,  Kazmi N,  Robinson TM,  Albanes D,  Aleksandrova K,  Berndt SI,  Timothy Bishop D,  Brenner H,  Buchanan DD,  Bueno-de-Mesquita B,  Campbell PT,  Castellví-Bel S,  Chan AT,  Chang-Claude J,  Ellingjord-Dale M,  Figueiredo JC,  Gallinger SJ,  Giles GG,  Giovannucci E,  Gruber SB,  Gsur A,  Hampe J,  Hampel H,  Harlid S,  Harrison TA,  Hoffmeister M,  Hopper JL,  Hsu L,  María Huerta J,  Huyghe JR,  Jenkins MA,  Keku TO,  Kühn T,  La Vecchia C,  Le Marchand L,  Li CI,  Li L,  Lindblom A,  Lindor NM,  Lynch B,  Markowitz SD,  Masala G,  May AM,  Milne R,  Monninkhof E,  Moreno L,  Moreno V,  Newcomb PA,  Offit K,  Perduca V,  Pharoah PDP,  Platz EA,  Potter JD,  Rennert G,  Riboli E,  Sánchez MJ,  Schmit SL,  Schoen RE,  Severi G,  Sieri S,  Slattery ML,  Song M,  Tangen CM,  Thibodeau SN,  Travis RC,  Trichopoulou A,  Ulrich CM,  van Duijnhoven FJB,  Van Guelpen B,  Vodicka P,  White E,  Wolk A,  Woods MO,  Wu AH,  Peters U,  Gunter MJ,  Murphy N
Journal: Nat Commun
Date: 2020 Jan 30
Branches: MEB, OEEB
PubMed ID: 32001714
PMC ID: not available
Abstract: Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.
Title: Risk of prostate cancer death following a low PSA level in the PLCO Trial.
Authors: Landy R,  Houghton LC,  Berg CD,  Grubb RL,  Katki HA,  Black A
Journal: Cancer Prev Res (Phila)
Date: 2020 Jan 29
Branches: BB, OD
PubMed ID: 31996370
PMC ID: not available
Abstract: Longer-than-annual screening intervals have been suggested to improve the balance of benefits and harms in prostate cancer screening. Many researchers, societies and guideline committees have suggested that screening intervals could depend on the prostate specific antigen (PSA) result. We analyzed data from men (N=33,897) aged 55-74yrs with a baseline PSA test in the intervention arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial (USA, 1993-2001). We estimated 5- and 10-year risks of aggressive cancer (Gleason ≥ 8 and/or Stage III/IV) and 15-year risks of prostate cancer mortality for men with baseline PSA ≤ 0.5ng/ml (N=4,862), ≤ 1ng/ml (N=15,110) and 1.01-2.5ng/ml (N=12,422). 217 men died from prostate cancer through 15yrs, though no men with PSA ≤ 1ng/ml died from prostate cancer within 5yrs (95% CI: 0.00%-0.03%). The 5-year incidence of aggressive disease was low (0.08%, 95% CI: 0.03%-0.12%) for men with PSA ≤ 1ng/ml, and higher for men with baseline PSA 1.01-2.5ng/ml (0.51%, 95% CI: 0.38-0.74). No men aged ≥ 65yrs with PSA ≤ 0.5ng/ml died from prostate cancer within 15yrs (95% CI: 0.00%-0.32%), and their 10-year incidence of aggressive disease was low (0.25%, 95% CI: 0.00%-0.53%). Compared to white men, black men with PSA ≤ 1ng/ml had higher 10-year rates of aggressive disease (1.6% vs. 0.4%, p < 0.01). 5-year screening intervals may be appropriate for the 45% of men with PSA ≤ 1ng/ml. Men aged ≥ 65yrs with PSA ≤ 0.5ng/ml could consider stopping screening. Substantial risk disparities suggest appropriate screening intervals could depend on race/ethnicity.
Title: 2,4-D exposure and urinary markers of oxidative DNA damage and lipid peroxidation: a longitudinal study.
Authors: Lerro CC,  Andreotti G,  Wong JY,  Blair A,  Rothman N,  Beane Freeman LE
Journal: Occup Environ Med
Date: 2020 Jan 29
Branches: OEEB
PubMed ID: 31996474
PMC ID: not available
Abstract: OBJECTIVE: 2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide that is commonly used commercially, agriculturally and residentially worldwide. There is concern about its potential for carcinogenicity based on studies in laboratory animals demonstrating the potential for induction of oxidative stress. We conducted a longitudinal biomarker study of 31 pesticide applicators in Kansas who heavily applied 2,4-D and 34 non-applicator controls. METHODS: We used multivariable generalised linear mixed-effect models to evaluate the association between urinary 2,4-D and natural log-transformed 8-iso prostaglandin F2α (8-isoprostane) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), adjusting for urinary creatinine, age, tobacco use and concomitant use of the herbicide picloram. RESULTS: Compared with non-applicator controls, urinary 2,4-D in the third quartile of exposure was associated with elevated 8-isoprostane (eβ=1.38, 95% CI 1.03 to 1.84). There was no association among the highest exposed and no exposure-response trend. 2,4-D exposure was not associated with 8-OHdG. Results were unchanged when restricted to participants who only applied 2,4-D (no picloram use). CONCLUSIONS: We did not find evidence that increasing 2,4-D exposure was associated with 8-isoprostane or 8-OHdG. Future work should carefully evaluate potential confounders of this association, such as diet and physical activity, as well as additional biological markers of oxidative stress and damage.
Title: In search of genetic factors predisposing to familial hairy cell leukemia (HCL): exome-sequencing of four multiplex HCL pedigrees.
Authors: Pemov A,  Pathak A,  Jones SJ,  Dewan R,  Merberg J,  Karra S,  Kim J,  Arons E,  Ravichandran S,  Luke BT,  Suman S,  Yeager M,  NCI DCEG Cancer Genomics Research Laboratory,  Dyer MJS,  Lynch HT,  Greene MH,  Caporaso NE,  Kreitman RJ,  Goldin LR,  Spinelli JJ,  Brooks-Wilson A,  McMaster ML,  Stewart DR
Journal: Leukemia
Date: 2020 Jan 28
Branches: CGB, CGR, OEEB
PubMed ID: 31992839
PMC ID: not available
Abstract:
Title: Misclassification of primary liver cancer in the Life Span Study of atomic bomb survivors.
Authors: French B,  Sadakane A,  Cologne J,  Mabuchi K,  Ozasa K,  Preston DL
Journal: Int J Cancer
Date: 2020 Jan 27
Branches: REB
PubMed ID: 31985032
PMC ID: not available
Abstract: Primary liver cancer is difficult to diagnose accurately at death, due to metastases from nearby organs and to concomitant diseases, such as chronic hepatitis and cirrhosis. Trends in diagnostic accuracy could affect radiation risk estimates for incident liver cancer by altering background rates or by impacting risk modification by sex and age. We quantified the potential impact of death-certificate inaccuracies on radiation risk estimates for liver cancer in the Life Span Study of atomic bomb survivors. True-positive and false-negative rates were obtained from a previous study that compared death-certificate causes of death with those based on pathological review, from 1958 to 1987. We assumed various scenarios for misclassification rates after 1988. We obtained estimated true positives and estimated false negatives by stratified sampling from Binomial distributions with probabilities given by the true-positive and false-negative rates, respectively. Poisson regression methods were applied to highly stratified person-year tables of corrected case counts and accrued person years. During the study period (1958-2009), there were 1,885 cases of liver cancer, which included 383 death-certificate-only cases; 1,283 cases with chronic liver disease as the underlying cause of death; and 150 death-certificate-only cases of pancreatic cancer among 105,444 study participants. Across the range of scenarios considered, radiation risk estimates based on corrected case counts were attenuated, on average, by 13-30%. Our results indicated that radiation risk estimates for liver cancer were potentially sensitive to death-certificate inaccuracies. Additional data are needed to inform misclassification rates in recent years. This article is protected by copyright. All rights reserved.
Title: Comorbidity and stage at diagnosis among lung cancer patients in the US military health system.
Authors: Lin J,  McGlynn KA,  Nations JA,  Shriver CD,  Zhu K
Journal: Cancer Causes Control
Date: 2020 Jan 27
Branches: MEB
PubMed ID: 31984449
PMC ID: not available
Abstract: PURPOSE: We investigated the association between comorbidities and stage at diagnosis among NSCLC patients in the US Military Health System (MHS), which provides universal health care to its beneficiaries. METHODS: The linked data from the Department of Defense's Central Cancer Registry (CCR) and the MHS Data Repository (MDR) were used. The study included 4768 patients with histologically confirmed primary NSCLC. Comorbid conditions were extracted from the MDR data. Comorbid conditions were those included in the Charlson Comorbidity Index (CCI) and were defined as a diagnosis during a 3-year time frame prior to the NSCLC diagnosis. Multivariable logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) of late stage (stages III and IV) versus early stage (stages I and II) in relation to pre-existing comorbidities. RESULTS: Compared to patients with no comorbidities, those with prior comorbidities tended to be less likely to have lung cancer diagnosed at late stage. When specific comorbidities were analyzed, decreased odds of being diagnosed at late stage were observed among those with chronic obstructive pulmonary disease (COPD) (adjusted OR 0.78, 95% CI 0.68 to 0.90). In contrast, patients with a congestive heart failure or a liver cirrhosis/chronic hepatitis had an increased likelihood of being diagnosed at late stage (adjusted OR 1.30, 95% CI 1.00 to 1.69 and adjusted OR 1.87, 95% CI 1.24 to 2.82, respectively). CONCLUSIONS: Among NSCLC patients in an equal access health system, the likelihood of late stage at diagnosis differed by specific comorbid diseases.
Title: Radiation risk of central nervous system tumors in the Life Span Study of atomic bomb survivors, 1958-2009.
Authors: Brenner AV,  Sugiyama H,  Preston DL,  Sakata R,  French B,  Sadakane A,  Cahoon EK,  Utada M,  Mabuchi K,  Ozasa K
Journal: Eur J Epidemiol
Date: 2020 Jan 25
Branches: REB
PubMed ID: 31982981
PMC ID: not available
Abstract: Radiation exposure is among the few factors known to be associated with risk of central nervous system (CNS) tumors. However, the patterns of radiation risk by histological type, sex or age are unclear. We evaluated radiation risks of first primary glioma, meningioma, schwannoma, and other or not otherwise specified (other/NOS) tumors in the Life Span Study cohort of atomic bomb survivors. Cases diagnosed between 1958 and 2009 were ascertained through population-based cancer registries in Hiroshima and Nagasaki. To estimate excess relative risk per Gy (ERR/Gy), we fit rate models using Poisson regression methods. There were 285 CNS tumors (67 gliomas, 107 meningiomas, 49 schwannomas, and 64 other/NOS tumors) among 105,444 individuals with radiation dose estimates to the brain contributing 3.1 million person-years of observation. Based on a simple linear model without effect modification, ERR/Gy was 1.67 (95% confidence interval, CI: 0.12 to 5.26) for glioma, 1.82 (95% CI: 0.51 to 4.30) for meningioma, 1.45 (95% CI: - 0.01 to 4.97) for schwannoma, and 1.40 (95% CI: 0.61 to 2.57) for all CNS tumors as a group. For each tumor type, the dose-response was consistent with linearity and appeared to be stronger among males than among females, particularly for meningioma (P = 0.045). There was also evidence that the ERR/Gy for schwannoma decreased with attained age (P = 0.002). More than 60 years after the bombings, radiation risks for CNS tumors continue to be elevated. Further follow-up is necessary to characterize the lifetime risks of specific CNS tumors following radiation exposure.
Title: Population frequency of Fanconi pathway gene variants and their association with survival after hematopoietic cell transplant for severe aplastic anemia.
Authors: McReynolds LJ,  Wang Y,  Thompson AS,  Ballew BJ,  Kim J,  Alter BP,  Hicks B,  Zhu B,  Jones K,  Spellman SR,  Wang T,  Lee SJ,  Savage SA,  Gadalla SM
Journal: Biol Blood Marrow Transplant
Date: 2020 Jan 23
Branches: BB, CGB, CGR, OD
PubMed ID: 31982544
PMC ID: not available
Abstract: Severe aplastic anemia (SAA) is most frequently immune mediated, however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal, and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by having two pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants/125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplant (HCT) (21 variants/730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in an FA genes in both groups (2.6 and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (HR=0.85, 95% CI=0.37-1.95, p=0.71), or post-HCT cancer risk (p=0.52). Our results show that the identification of a germline monoallelic deleterious variant in an FA gene, in a patient with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.
Title: Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.
Authors: Savage SA,  Viard M,  O'hUigin C,  Zhou W,  Yeager M,  Li SA,  Wang T,  Ramsuran V,  Vince N,  Vogt A,  Hicks B,  Burdett L,  Chung C,  Dean M,  de Andrade KC,  Freedman ND,  Berndt SI,  Rothman N,  Lan Q,  Cerhan JR,  Slager SL,  Zhang Y,  Teras LR,  Haagenson M,  Chanock SJ,  Spellman SR,  Wang Y,  Willis A,  Askar M,  Lee SJ,  Carrington M,  Gadalla SM
Journal: Am J Hum Genet
Date: 2020 Jan 23
Branches: CGB, CGR, LTG, MEB, OD, OEEB
PubMed ID: 32004448
PMC ID: not available
Abstract: Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.
Title: Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol.
Authors: Troisi R,  Palmer JR,  Hatch EE,  Strohsnitter WC,  Huo D,  Hyer M,  Fredriksen-Goldsen KI,  Hoover R,  Titus L
Journal: Arch Sex Behav
Date: 2020 Jan 23
Branches: EBP
PubMed ID: 31975033
PMC ID: not available
Abstract: We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who participated in a study of prenatal DES exposure. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models adjusted for birth year, study cohort, and education. Among women, the OR for DES in relation to reporting sexual orientation identity as nonheterosexual was 0.61 (95% CI 0.40-0.92) primarily due to a strong inverse association with a lesbian identity (OR 0.44, 95% CI 0.25-0.76). Among men, the OR for DES in relation to reporting a nonheterosexual sexual orientation identity was 1.4 (95% CI 0.82-2.4), and ORs were similar for having a gay identity (1.4, 95% CI 0.72-2.85) and bisexual identity (1.4, 95% CI 0.57-3.5). Only five individuals reported a gender identity not conforming to that assigned at birth, preventing meaningful analysis. Women who were prenatally exposed to DES were less likely to have a lesbian or bisexual orientation, while DES-exposed men were somewhat more likely to report being gay or bisexual, but estimates were imprecise.
Title: Topographical classification of dose distributions: implications for control for worker exposure.
Authors: Bragin Y,  Chizhov K,  Sneve M,  Tsovyanov A,  Shandala N,  Siegien K,  Smith G,  Tesnov I,  Krasnoschekov A,  Ksenofontov A,  Kryanev A,  Drozdovitch V,  Kryuchkov V
Journal: J Radiol Prot
Date: 2020 Jan 22
Branches: REB
PubMed ID: 31968313
PMC ID: not available
Abstract: This paper deals with classification of dose distributions of nuclear workers based on antikurtosis (Q) and entropy coefficient (K) and their relationship presented in QK-diagrams. It is shown that dispersion stabilization of a wide range of input data requires building and analyzing QK-diagrams for distributions of logarithms of individual doses. Actual dose distributions for emergency and occupational exposure situations were then considered, as well as doses for one day of work during clean-up and routine activities. It is shown that in all cases, three types of distributions of individual dose logarithms were present: normal, Weibull and Chapeau. The location of the representation point of a dose distribution reflects the degree of dose control of the group of workers whose individual doses are collectively displayed on the QK-diagram. A point with coordinates (K = 0.577, Q = 2.066) on the QK-diagram corresponds to the absence of this process control. The more the representation point of the analyzed distribution of the logarithms of individual dose of a given contingent of workers deviates from the point of the lognormal distribution, the more there was intervention in the process of individual dose accumulation. Thus, QK-diagrams could be used to develop a dose control function. It is shown that the Hybrid Lognormal distribution, which is widely used in the field of radiation safety for the purpose of approximation of real dose distributions, cannot satisfactorily describe many dose distributions in case of aftermath operations and occupational exposure.
Title: Recent Decline in Hepatocellular Carcinoma Rates in the United States.
Authors: Shiels MS,  O'Brien TR
Journal: Gastroenterology
Date: 2020 Jan 18
Branches: IIB
PubMed ID: 31962125
PMC ID: not available
Abstract:
Title: Relationship of Serum Progesterone and Progesterone Metabolites with Mammographic Breast Density and Terminal Ductal Lobular Unit Involution among Women Undergoing Diagnostic Breast Biopsy.
Authors: Hada M,  Oh H,  Fan S,  Falk RT,  Geller B,  Vacek P,  Weaver D,  Shepherd J,  Wang J,  Fan B,  Herschorn S,  Brinton LA,  Xu X,  Sherman ME,  Trabert B,  Gierach GL
Journal: J Clin Med
Date: 2020 Jan 17
Branches: ITEB, MEB, OD
PubMed ID: 31963437
PMC ID: not available
Abstract: The association of progesterone/progesterone metabolites with elevated mammographic breast density (MBD) and delayed age-related terminal duct lobular unit (TDLU) involution, strong breast cancer risk factors, has received limited attention. Using a reliable liquid chromatography-tandem mass-spectrometry assay, we quantified serum progesterone/progesterone metabolites and explored cross-sectional relationships with MBD and TDLU involution among women, ages 40-65, undergoing diagnostic breast biopsy. Quantitative MBD measures were estimated in pre-biopsy digital mammograms. TDLU involution was quantified in diagnostic biopsies. Adjusted partial correlations and trends across MBD/TDLU categories were calculated. Pregnenolone was positively associated with percent MBD-area (MBD-A, rho: 0.30; p-trend = 0.01) among premenopausal luteal phase women. Progesterone tended to be positively associated with percent MBD-A among luteal phase (rho: 0.26; p-trend = 0.07) and postmenopausal (rho: 0.17; p-trend = 0.04) women. Consistent with experimental data, implicating an elevated 5α-pregnanes/3α-dihydroprogesterone (5αP/3αHP) metabolite ratio in breast cancer, higher 5αP/3αHP was associated with elevated percent MBD-A among luteal phase (rho: 0.29; p-trend = 0.08), but not postmenopausal women. This exploratory analysis provided some evidence that endogenous progesterone and progesterone metabolites might be correlated with MBD, a strong breast cancer risk factor, in both pre- and postmenopausal women undergoing breast biopsy. Additional studies are needed to understand the role of progesterone/progesterone metabolites in breast tissue composition and breast cancer risk.
Title: A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.
Authors: Escala-Garcia M,  Abraham J,  Andrulis IL,  Anton-Culver H,  Arndt V,  Ashworth A,  Auer PL,  Auvinen P,  Beckmann MW,  Beesley J,  Behrens S,  Benitez J,  Bermisheva M,  Blomqvist C,  Blot W,  Bogdanova NV,  Bojesen SE,  Bolla MK,  Børresen-Dale AL,  Brauch H,  Brenner H,  Brucker SY,  Burwinkel B,  Caldas C,  Canzian F,  Chang-Claude J,  Chanock SJ,  Chin SF,  Clarke CL,  Couch FJ,  Cox A,  Cross SS,  Czene K,  Daly MB,  Dennis J,  Devilee P,  Dunn JA,  Dunning AM,  Dwek M,  Earl HM,  Eccles DM,  Eliassen AH,  Ellberg C,  Evans DG,  Fasching PA,  Figueroa J,  Flyger H,  Gago-Dominguez M,  Gapstur SM,  García-Closas M,  García-Sáenz JA,  Gaudet MM,  George A,  Giles GG,  Goldgar DE,  González-Neira A,  Grip M,  Guénel P,  Guo Q,  Haiman CA,  HÃ¥kansson N,  Hamann U,  Harrington PA,  Hiller L,  Hooning MJ,  Hopper JL,  Howell A,  Huang CS,  Huang G,  Hunter DJ,  Jakubowska A,  John EM,  Kaaks R,  Kapoor PM,  Keeman R,  Kitahara CM,  Koppert LB,  Kraft P,  Kristensen VN,  Lambrechts D,  Le Marchand L,  Lejbkowicz F,  Lindblom A,  Lubiński J,  Mannermaa A,  Manoochehri M,  Manoukian S,  Margolin S,  Martinez ME,  Maurer T,  Mavroudis D,  Meindl A,  Milne RL,  Mulligan AM,  Neuhausen SL,  Nevanlinna H,  Newman WG,  Olshan AF,  Olson JE,  Olsson H,  Orr N,  Peterlongo P,  Petridis C,  Prentice RL,  Presneau N,  Punie K,  Ramachandran D,  Rennert G,  Romero A,  Sachchithananthan M,  Saloustros E,  Sawyer EJ,  Schmutzler RK,  Schwentner L,  Scott C,  Simard J,  Sohn C,  Southey MC,  Swerdlow AJ,  Tamimi RM,  Tapper WJ,  Teixeira MR,  Terry MB,  Thorne H,  Tollenaar RAEM,  Tomlinson I,  Troester MA,  Truong T,  Turnbull C,  Vachon CM,  van der Kolk LE,  Wang Q,  Winqvist R,  Wolk A,  Yang XR,  Ziogas A,  Pharoah PDP,  Hall P,  Wessels LFA,  Chenevix-Trench G,  Bader GD,  Dörk T,  Easton DF,  Canisius S,  Schmidt MK
Journal: Nat Commun
Date: 2020 Jan 16
Branches: CGR, ITEB, OD, REB
PubMed ID: 31949161
PMC ID: PMC6965101
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
Title: Among Individuals Irradiated for Benign Conditions in Childhood, Developing Thyroid Cancer Does Not Affect All-Cause Survival.
Authors: Vydro L,  Kitahara CM,  Lubin JH,  Schneider AB,  Mihailescu DV
Journal: Thyroid
Date: 2020 Jan 16
Branches: BB, REB
PubMed ID: 31797741
PMC ID: not available
Abstract: Background: Whether radiation-induced thyroid cancer affects survival rates has not been clearly elucidated. Survival could be affected by the thyroid cancer itself, its treatment, or by being a sign of susceptibility to other cancers. The objective of the current study was to determine if the development of thyroid cancer is associated with a differential survival in radiation-exposed individuals. Methods: We conducted a matched prospective cohort mortality follow-up study based on data from a cohort of 4296 individuals who were irradiated predominantly for enlarged tonsils during their childhood (between 1939 and 1962) and were prospectively followed since 1974. The study matched an irradiated subject who developed (was exposed to) thyroid cancer (a "case") and two irradiated subjects, who had not developed (were not exposed to) thyroid cancer ("controls") by the time of case incidence. The two controls were randomly matched to cases by sex, year of birth, age at radiation treatment, and radiation dose. Then, using a stratified Cox analysis, we compared survival time from the date of thyroid cancer diagnosis or time of selection to either date of death or the end of the observation period (December 31, 2016). Vital status and causes of death were determined using the National Death Index (1979-2016), the Social Security Death Index (1974-1979), and study files. Cause of death was categorized as cardiovascular, malignancy, or other. Results: A total of 1008 subjects were included in the analysis, including 353 thyroid cancer cases. At the end of the study period, 162 of 655 (24.7%) of individuals without thyroid cancer had died compared with 100 of 353 (28.3%) of the subjects with thyroid cancer. The hazard ratio (HR) for all-cause mortality, comparing the thyroid cancer cases to controls, was close to unity (HR = 1.01 [0.77-1.33]). HRs remained insignificant after eliminating matched sets with microcarcinomas, defined as tumor size <10 mm (HR = 1.39 [0.96-2.03]). Distribution of the causes of death taking into account age and the time of observation differed between cases and controls (p < 0.05). Neither increased cardiovascular-related nor malignancy-related mortality was associated with radiation-induced thyroid cancer. Conclusions: Among individuals irradiated for benign conditions in childhood, development of thyroid cancer was not associated with decreased all-cause survival.
Title: Gynecologic and reproductive health in patients with pathogenic germline variants in DICER1.
Authors: Merideth MA,  Harney LA,  Vyas N,  Bachi A,  Carr AG,  Hill DA,  Dehner LP,  Schultz KAP,  Stewart DR,  Stratton P
Journal: Gynecol Oncol
Date: 2020 Jan 15
Branches: CGB
PubMed ID: 31952842
PMC ID: not available
Abstract: OBJECTIVE: Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described. METHODS: All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review. RESULTS: Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy. CONCLUSION: In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.
Title: DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.
Authors: Pardini B,  Corrado A,  Paolicchi E,  Cugliari G,  Berndt SI,  Bezieau S,  Bien SA,  Brenner H,  Caan BJ,  Campbell PT,  Casey G,  Chan AT,  Chang-Claude J,  Cotterchio M,  Gala M,  Gallinger SJ,  Haile RW,  Harrison TA,  Hayes RB,  Hoffmeister M,  Hopper JL,  Hsu L,  Huyghe J,  Jenkins MA,  Le Marchand L,  Lin Y,  Lindor NM,  Nan H,  Newcomb PA,  Ogino S,  Potter JD,  Schoen RE,  Slattery ML,  White E,  Vodickova L,  Vymetalkova V,  Vodicka P,  Gemignani F,  Peters U,  Naccarati A,  Landi S
Journal: Int J Cancer
Date: 2020 Jan 15
Branches: OEEB
PubMed ID: 31209889
PMC ID: not available
Abstract: Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.
Title: Penetrance of Different Cancer Types in Families with Li-Fraumeni Syndrome: A Validation Study Using Multicenter Cohorts.
Authors: Shin SJ,  Dodd-Eaton EB,  Peng G,  Bojadzieva J,  Chen J,  Amos CI,  Frone MN,  Khincha PP,  Mai PL,  Savage SA,  Ballinger ML,  Thomas DM,  Yuan Y,  Strong LC,  Wang W
Journal: Cancer Res
Date: 2020 Jan 15
Branches: CGB, OD
PubMed ID: 31719101
PMC ID: PMC6980689
Abstract: Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal-dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. The previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a TP53 mutation carrier. However, an accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals. Here, we developed a competing risk-based statistical model that incorporates the pedigree structure efficiently into the penetrance estimation and corrects for ascertainment bias while also increasing the effective sample size of this rare population. This enabled successful estimation of TP53 penetrance for three LFS cancer types: breast (BR), sarcoma (SA), and others (OT), from 186 pediatric sarcoma families collected at MD Anderson Cancer Center (Houston, TX). Penetrance validation was performed on a combined dataset of two clinically ascertained family cohorts with cancer to overcome internal bias in each (total number of families = 668). The age-dependent onset probability distributions of specific cancer types were different. For breast cancer, the TP53 penetrance went up at an earlier age than the reported BRCA1/2 penetrance. The prediction performance of the penetrance estimates was validated by the combined independent cohorts (BR = 85, SA = 540, and OT = 158). Area under the ROC curves (AUC) were 0.92 (BR), 0.75 (SA), and 0.81 (OT). The new penetrance estimates have been incorporated into the current LFSPRO R package to provide risk estimates for the diagnosis of breast cancer, sarcoma, or other cancers. SIGNIFICANCE: These findings provide specific penetrance estimates for LFS-associated cancers, which will likely impact the management of families at high risk of LFS.See related article by Shin et al., p. 347.
Title: Modeling repeated labor curves in consecutive pregnancies: Individualized prediction of labor progression from previous pregnancy data.
Authors: Buhule OD,  Choo-Wosoba H,  Albert PS
Journal: Stat Med
Date: 2020 Jan 14
Branches: BB
PubMed ID: 31943255
PMC ID: not available
Abstract: The measurement of cervical dilation of a pregnant woman is used to monitor the progression of labor until 10 cm when pushing begins. There is anecdotal evidence that labor tracks across repeated pregnancies; moreover, no statistical methodology has been developed to address this important issue, which can help obstetricians make more informed clinical decisions about an individual woman's progression. Motivated by the NICHD Consecutive Pregnancies Study (CPS), we propose new methodology for analyzing labor curves across consecutive pregnancies. Our focus is both on studying the correlation between repeated labor curves on the same woman and on using the cervical dilation data from prior pregnancies to predict subsequent labor curves. We propose a hierarchical random effects model with a random change point that characterizes repeated labor curves within and between women to address these issues. We employ Bayesian methodology for parameter estimation and prediction. Model diagnostics to examine the appropriateness of the hierarchical random effects structure for characterizing the dependence structure across consecutive pregnancies are also proposed. The methodology was used in analyzing the CPS data and in developing a predictor for labor progression that can be used in clinical practice.
Title: A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.
Authors: Du Z,  Weinhold N,  Song GC,  Rand KA,  Van Den Berg DJ,  Hwang AE,  Sheng X,  Hom V,  Ailawadhi S,  Nooka AK,  Singhal S,  Pawlish K,  Peters ES,  Bock C,  Mohrbacher A,  Stram A,  Berndt SI,  Blot WJ,  Casey G,  Stevens VL,  Kittles R,  Goodman PJ,  Diver WR,  Hennis A,  Nemesure B,  Klein EA,  Rybicki BA,  Stanford JL,  Witte JS,  Signorello L,  John EM,  Bernstein L,  Stroup AM,  Stephens OW,  Zangari M,  Van Rhee F,  Olshan A,  Zheng W,  Hu JJ,  Ziegler R,  Nyante SJ,  Ingles SA,  Press MF,  Carpten JD,  Chanock SJ,  Mehta J,  Colditz GA,  Wolf J,  Martin TG,  Tomasson M,  Fiala MA,  Terebelo H,  Janakiraman N,  Kolonel L,  Anderson KC,  Le Marchand L,  Auclair D,  Chiu BC,  Ziv E,  Stram D,  Vij R,  Bernal-Mizrachi L,  Morgan GJ,  Zonder JA,  Huff CA,  Lonial S,  Orlowski RZ,  Conti DV,  Haiman CA,  Cozen W
Journal: Blood Adv
Date: 2020 Jan 14
Branches: CGR, OD, OEEB
PubMed ID: 31935283
PMC ID: PMC6960456
Abstract: Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.
Title: Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank.
Authors: Irvin S,  Weiderpass E,  Stanczyk FZ,  Brinton LA,  Trabert B,  Langseth H,  Wentzensen N
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2020 Jan 13
Branches: CGB, MEB, OD
PubMed ID: 31932414
PMC ID: not available
Abstract: BACKGROUND: Reproductive factors, including parity, breastfeeding and contraceptive use affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of Anti-Mullerian Hormone, Follicle Stimulating Hormone and Inhibin B with ovarian cancer risk. METHODS: Our study included 370 women from the Janus Serum Bank, including 54 Type 1 and 82 Type 2 invasive epithelial ovarian cancers and 49 borderline tumors and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (Type 1 and 2). RESULTS: Inhibin B was associated with increased risk of ovarian cancer overall (OR 1.97 95% CI 1.14-3.39, ptrend 0.05) and with type 1 ovarian (OR 3.10, 95% CI 1.04-9.23, ptrend 0.06). FSH was not associated with ovarian cancer risk overall but higher FSH was associated with type 2 ovarian cancers (OR 2.78, 95% CI 1.05-7.38). AMH was not associated with ovarian cancer risk. CONCLUSIONS: FSH and Inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. IMPACT: Associations between prospectively collected AMH, FSH and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of pre-menopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.
Title: The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: an analysis from the Ovarian Cancer Cohort Consortium (OC3).
Authors: Trabert B,  Tworoger SS,  O'Brien KM,  Townsend MK,  Fortner RT,  Iversen ES,  Hartge P,  White E,  Amiano P,  Arslan AA,  Bernstein L,  Brinton LA,  Buring JE,  Dossus L,  Fraser GE,  Gaudet MM,  Giles GG,  Gram IT,  Harris HR,  Hoffman Bolton J,  Idahl A,  Jones ME,  Kaaks R,  Kirsh VA,  Knutsen SF,  Kvaskoff M,  Lacey JV,  Lee IM,  Milne RL,  Onland-Moret NC,  Overvad K,  Patel AV,  Peters U,  Poynter JN,  Riboli E,  Robien K,  Rohan TE,  Sandler DP,  Schairer C,  Schouten LJ,  Setiawan VW,  Swerdlow AJ,  Travis RC,  Trichopoulou A,  van den Brandt PA,  Visvanathan K,  Wilkens LR,  Wolk A,  Zeleniuch-Jacquotte A,  Wentzensen N
Journal: Cancer Res
Date: 2020 Jan 13
Branches: CGB, MEB, OD
PubMed ID: 31932455
PMC ID: not available
Abstract: Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per five-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity=0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity=0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from ~300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk which cumulates through life, suggesting this as an important area for identifying intervention strategies.
Title: APOBEC3B expression in breast cancer cell lines and tumors depends on the estrogen receptor status.
Authors: Udquim KI,  Zettelmeyer C,  Banday AR,  Lin SH,  Prokunina-Olsson L
Journal: Carcinogenesis
Date: 2020 Jan 13
Branches: LTG
PubMed ID: 31930332
PMC ID: not available
Abstract: Increased exposure to estrogen is associated with an elevated risk of breast cancer. Considering estrogen as a possible mutagen, we hypothesized that exposure to estrogen alone or in combination with the DNA-damaging chemotherapy drug, cisplatin, could induce expression of genes encoding enzymes involved in APOBEC-mediated mutagenesis. To test this hypothesis, we measured the expression of APOBEC3A (A3A) and APOBEC3B (A3B) genes in two breast cancer cell lines treated with estradiol, cisplatin, or their combination. These cell lines, T-47D (ER+) and MDA-MB-231 (ER-), differed by the status of the estrogen receptor (ER). Expression of A3A was not detectable in any conditions tested, while A3B expression was induced by treatment with cisplatin and estradiol in ER+ cells but was not affected by estradiol in ER- cells. In The Cancer Genome Atlas (TCGA), expression of A3B was significantly associated with genotypes of a regulatory germline variant rs17000526 upstream of the APOBEC3 cluster in 116 ER- breast tumors (p= 0.006) but not in 387 ER+ tumors (p= 0.48). In conclusion, we show that in breast cancer cell lines, A3B expression was induced by estradiol in ER+ cells and by cisplatin regardless of ER status. In ER+ breast tumors, the effect of estrogen may be masking the association of rs17000526 with A3B expression, which was apparent in ER- tumors. Our results provide new insights into the differential etiology of ER+ and ER- breast cancer and the possible role of A3B in this process through a mitogenic rather than the mutagenic activity of estrogen.
Title: Trends and Patterns of Testosterone Therapy Among US Male Medicare Beneficiaries, 1999-2014.
Authors: Zhou CK,  Advani S,  Chaloux M,  Gibson JT,  Yu M,  Bradley M,  Hoover RN,  Cook MB
Journal: J Urol
Date: 2020 Jan 13
Branches: EBP, MEB
PubMed ID: 31928462
PMC ID: not available
Abstract: PURPOSE: We explored the Medicare database (1999-2014) to provide a comprehensive assessment of testosterone therapy (TT) patterns in the older US male population. MATERIALS AND METHODS: We estimated annual age-standardized incidence (new users) and prevalence (existing users) of TT according to demographic characteristics, comorbidities, and potential indications. RESULTS: There were 392,698 incident TT users during 88 million person-years. TT users were predominantly younger, white non-Hispanic, and located in South and West US Census regions. On average, TT dramatically increased during 2007-2014 (average annual percent change=15.5%), despite a decrease in 2014. In 2014, the most common recorded potential indications for any TT were hypogonadism (48%), fatigue (18%), erectile dysfunction (15%), depression (4%), and psychosexual dysfunction (1%). Laboratory tests to measure circulating testosterone concentrations for TT were infrequent with 35% having had at least one testosterone test in the 120 days preceding TT, 4% the recommended two pre-TT tests, and 16% at least one pre-TT test and at least one post-TT test. CONCLUSIONS: TT remains common in the older US male population, despite a recent decrease. Although TT prescriptions are predominantly for hypogonadism, a substantial proportion appear to be for less specific conditions. Testosterone tests amongst men prescribed TT appear to be infrequent.
Title: LDpop: an interactive online tool to calculate and visualize geographic LD patterns.
Authors: Alexander TA,  Machiela MJ
Journal: BMC Bioinformatics
Date: 2020 Jan 10
Branches: ITEB
PubMed ID: 31924160
PMC ID: PMC6954550
Abstract: BACKGROUND: Linkage disequilibrium (LD)-the non-random association of alleles at different loci-defines population-specific haplotypes which vary by genomic ancestry. Assessment of allelic frequencies and LD patterns from a variety of ancestral populations enables researchers to better understand population histories as well as improve genetic understanding of diseases in which risk varies by ethnicity. RESULTS: We created an interactive web module which allows for quick geographic visualization of linkage disequilibrium (LD) patterns between two user-specified germline variants across geographic populations included in the 1000 Genomes Project. Interactive maps and a downloadable, sortable summary table allow researchers to easily compute and compare allele frequencies and LD statistics of dbSNP catalogued variants. The geographic mapping of each SNP's allele frequencies by population as well as visualization of LD statistics allows the user to easily trace geographic allelic correlation patterns and examine population-specific differences. CONCLUSIONS: LDpop is a free and publicly available cross-platform web tool which can be accessed online at https://ldlink.nci.nih.gov/?tab=ldpop.
Title: Cigarette smoking increases the risk of nasopharyngeal carcinoma through the elevated level of IgA antibody against Epstein-Barr virus capsid antigen: A mediation analysis.
Authors: Hsu WL,  Chien YC,  Huang YT,  Yu KJ,  Ko JY,  Lin CY,  Tsou YA,  Leu YS,  Liao LJ,  Chang YL,  Su JY,  Liu Z,  Wang CP,  Terng SD,  Hua CH,  Lee JC,  Yang TL,  Kate Hsiao CH,  Wu MS,  Tsai MH,  Liu MJ,  Lou PJ,  Hildesheim A,  Chen CJ,  GEV-NPC Study Group
Journal: Cancer Med
Date: 2020 Jan 10
Branches: IIB
PubMed ID: 31925935
PMC ID: not available
Abstract: BACKGROUND: The study aims are to evaluate the associations between nasopharyngeal carcinoma (NPC) risk and cigarette smoking and to explore the effects of cigarette smoking on Epstein-Barr virus (EBV) infection for NPC risk. METHODS: 1235 male NPC cases and 1262 hospital-based male controls matched to cases were recruited across six collaborative hospitals between 2010 and 2014. Using a standardized questionnaire, information on cigarette smoking and other potential risk factors for NPC was obtained. Blood was collected and used for anti-EBV VCA IgA and anti-EBV EA-EBNA1 IgA testing using standard methods. Unconditional logistic regression analysis was used to estimate odds ratio (OR) with 95% confidence interval (CI) for each risk factor after adjusting for confounders. RESULTS: 63.6% of cases and 44.0% of controls reported ever smoking cigarettes. After full adjustment, current smokers had a significant 1.60-fold (95% CI = 1.30-1.97) and former smokers a borderline significant 1.27-fold (95% CI = 1.00-1.60) increased NPC risk compared to never smokers. NPC risk increased with increasing duration, intensity, and pack-years of cigarette smoking but not with age at smoking initiation. Among controls, anti-EBV VCA IgA seropositivity rate was higher in current smokers than never smokers (14.0% vs 8.4%; OR = 1.82; 95% CI = 1.19-2.79). Mediation analyses showed that more than 90% of the cigarette smoking effect on NPC risk is mediated through anti-EBV VCA IgA. CONCLUSION: This study confirms the association between long-term cigarette smoking and NPC and demonstrates that current smoking is associated with seropositivity of anti-EBV VCA IgA antibodies.
Title: Land use regression models for ultrafine particles, fine particles, and black carbon in Southern California.
Authors: Jones RR,  Hoek G,  Fisher JA,  Hasheminassab S,  Wang D,  Ward MH,  Sioutas C,  Vermeulen R,  Silverman DT
Journal: Sci Total Environ
Date: 2020 Jan 10
Branches: OEEB
PubMed ID: 31793436
PMC ID: not available
Abstract: Exposure models are needed to evaluate health effects of long-term exposure to ambient ultrafine particles (UFP; <0.1 μm) and to disentangle their association from other pollutants, particularly PM2.5 (<2.5 μm). We developed land use regression (LUR) models to support UFP exposure assessment in the Los Angeles Ultrafines Study, a cohort in Southern California. We conducted a short-term measurement campaign in Los Angeles and parts of Riverside and Orange counties to measure UFP, PM2.5, and black carbon (BC), collecting three 30-minute average measurements at 215 sites across three seasons. We averaged concentrations for each site and evaluated geographic predictors including traffic intensity, distance to airports, land use, and population and building density by supervised stepwise selection to develop models. UFP and PM2.5 measurements (r = 0.001) and predictions (r = 0.05) were uncorrelated at the sites. UFP model explained variance was robust (R2 = 0.66) and 10-fold cross-validation indicated good performance (R2 = 0.59). Explained variation was moderate for PM2.5 (R2 = 0.47) and BC (R2 = 0.38). In the cohort, we predicted a 2.3-fold exposure contrast from the 5th to 95th percentiles for all three pollutants. The correlation between modeled UFP and PM2.5 at cohort residences was weak (r = 0.28), although higher than between measured levels. LUR models, particularly for UFP, were successfully developed and predicted reasonable exposure contrasts.
Title: Gallbladder and extrahepatic bile duct cancers in the Americas: Incidence and mortality patterns and trends.
Authors: Miranda-Filho A,  Piñeros M,  Ferreccio C,  Adsay V,  Soerjomataram I,  Bray F,  Koshiol J
Journal: Int J Cancer
Date: 2020 Jan 10
Branches: IIB
PubMed ID: 31922259
PMC ID: not available
Abstract: Trends in gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from International Agency for Research on Cancer (IARC) GLOBOCAN database for 185 countries. Recorded registry-based incidence from 13 countries was extracted from IARCs Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7) and Peru (6.0). In the US, the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, US Whites and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increase in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.
Title: High Dietary Intake of Vegetable or Polyunsaturated Fats is Associated With Reduced Risk of Hepatocellular Carcinoma.
Authors: Yang W,  Sui J,  Ma Y,  Simon TG,  Petrick JL,  Lai M,  McGlynn KA,  Campbell PT,  Giovannucci EL,  Chan AT,  Zhang X
Journal: Clin Gastroenterol Hepatol
Date: 2020 Jan 9
Branches: MEB
PubMed ID: 31927110
PMC ID: not available
Abstract: BACKGROUND & AIMS: We investigated associations of intake of total fats, specific dietary fats, and fats from different food sources with risk of hepatocellular carcinoma (HCC) using data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). METHODS: We analyzed data from a total of 138,483 women and men who participated in the NHS or HPFS. A validated semi-quantitative food frequency questionnaire was sent to NHS participants in 1980, 1984, 1986, and every 4 years thereafter; dietary information was collected from participants in the HPFS in 1986 and every 4 years thereafter. Multivariable hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression. RESULTS: After an average follow-up time of 26.6 years, 160 incident HCC cases were documented. Although there was a non-significant association between total fat intake and HCC, intake of vegetable fats reduced risk of HCC (HR for the highest vs lowest quartile, 0.61; 95% CI, 0.39-0.96; Ptrend=.02), but not animal or dairy fats. Replacing animal or dairy fats with an equivalent amount of vegetable fats was associated with a lower risk of HCC (HR per 1 standard deviation, 0.79; 95% CI, 0.65-0.97). Among fat subtypes, monounsaturated and polyunsaturated fatty acids, including n-3 (HR, 0.63; 95% CI, 0.41-0.96; Ptrend=.14) and n-6 polyunsaturated fatty acids (HR, 0.54; 95% CI, 0.34-0.86; Ptrend=.02), were inversely associated with risk of HCC. Higher ratios of monounsaturated or polyunsaturated fat to saturated fat were inversely associated with HCC risk (all Ptrend≤.02). In addition, when replacing saturated fats with monounsaturated or polyunsaturated fats, the HR per 1 standard deviation was 0.77 (95% CI, 0.64-0.92). CONCLUSIONS: In an analysis of data from 2 large cohort studies, we found higher intake of vegetable fats and polyunsaturated fats to be associated with lower risk of HCC. Replacing animal or dairy fats with vegetable fats, or replacing saturated fats with monounsaturated or polyunsaturated fats, was associated with reduced risk of HCC.
Title: A Transcriptome-Wide Association Study (TWAS) Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.
Authors: Zhong J,  Jermusyk A,  Wu L,  Hoskins JW,  Collins I,  Mocci E,  Zhang M,  Song L,  Chung CC,  Zhang T,  Xiao W,  Albanes D,  Andreotti G,  Arslan AA,  Babic A,  Bamlet WR,  Beane-Freeman L,  Berndt S,  Borgida A,  Bracci PM,  Brais L,  Brennan P,  Bueno-de-Mesquita B,  Buring J,  Canzian F,  Childs EJ,  Cotterchio M,  Du M,  Duell EJ,  Fuchs C,  Gallinger S,  Gaziano JM,  Giles GG,  Giovannucci E,  Goggins M,  Goodman GE,  Goodman PJ,  Haiman C,  Hartge P,  Hasan M,  Helzlsouer KJ,  Holly EA,  Klein EA,  Kogevinas M,  Kurtz RJ,  LeMarchand L,  Malats N,  Männistö S,  Milne R,  Neale RE,  Ng K,  Obazee O,  Oberg AL,  Orlow I,  Patel AV,  Peters U,  Porta M,  Rothman N,  Scelo G,  Sesso HD,  Severi G,  Sieri S,  Silverman D,  Sund M,  Tjønneland A,  Thornquist MD,  Tobias GS,  Trichopoulou A,  Van Den Eeden SK,  Visvanathan K,  Wactawski-Wende J,  Wentzensen N,  White E,  Yu H,  Yuan C,  Zeleniuch-Jacquotte A,  Hoover R,  Brown K,  Kooperberg C,  Risch HA,  Jacobs EJ,  Li D,  Yu K,  Shu XO,  Chanock SJ,  Wolpin BM,  Stolzenberg-Solomon RZ,  Chatterjee N,  Klein AP,  Smith JP,  Kraft P,  Shi J,  Petersen GM,  Zheng W,  Amundadottir LT
Journal: J Natl Cancer Inst
Date: 2020 Jan 9
Branches: BB, CGB, CGR, EBP, ITEB, LTG, MEB, OD, OEEB
PubMed ID: 31917448
PMC ID: not available
Abstract: BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
Title: Opiate and tobacco use and exposure to carcinogens and toxicants in Golestan Cohort Study.
Authors: Etemadi A,  Poustchi H,  Calafat AM,  Blount BC,  De Jesus VR,  Wang L,  Pourshams A,  Shakeri R,  Inoue-Choi M,  Shiels MS,  Roshandel G,  Murphy G,  Sosnoff CS,  Bhandari D,  Feng J,  Xia B,  Wang Y,  Meng L,  Kamangar F,  Brennan P,  Boffetta P,  Dawsey SM,  Abnet CC,  Malekzadeh R,  Freedman ND
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2020 Jan 8
Branches: IIB, MEB
PubMed ID: 31915141
PMC ID: not available
Abstract: BACKGROUND: There is little information on human exposure to carcinogens and toxicants related to opiate use, alone or combined with tobacco. METHODS: Among male participants of the Golestan Cohort Study in Northeast Iran, we studied 28 never users of either opiates or tobacco, 33 exclusive cigarette smokers, 23 exclusive users of smoked opiates, and 30 opiate users who also smoked cigarettes (dual users; 21 smoked opiates and 9 ingested them). We quantified urinary concentrations of 39 exposure biomarkers: tobacco alkaloids, tobacco specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs) and used decomposition to parse out the share of the biomarker concentrations explained by opiate use and nicotine dose. RESULTS: Dual users had the highest concentrations of all biomarkers, but exclusive cigarette smokers and exclusive opiate users had substantially higher concentrations of PAH and VOC biomarkers than never users. Decomposition analysis showed that opiate use contributed a larger part of the PAH concentrations than nicotine dose, and the sum of 2- and 3-hydroxyphenanthrene (∑2,3-phe) resulted almost completely from opiate use. Two acrylamide metabolites, a 1,3-butadiene metabolite, and a dimethylformamide metabolite were more strongly explained by opiate use. Acrylamide metabolites and ∑2,3-phe were significantly higher in opiate smokers than opiate eaters; other biomarkers did not vary by the route of opiate intake. CONCLUSION: Both cigarette smokers and opiate users (by smoking or ingestion) were exposed to many toxicants and carcinogens. IMPACT: This high exposure, particularly among dual opiates and cigarette users can have substantial global public health impact.
Title: Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies.
Authors: Gross AM,  Frone M,  Gripp KW,  Gelb BD,  Schoyer L,  Schill L,  Stronach B,  Biesecker LG,  Esposito D,  Hernandez ER,  Legius E,  Loh ML,  Martin S,  Morrison DK,  Rauen KA,  Wolters PL,  Zand D,  McCormick F,  Savage SA,  Stewart DR,  Widemann BC,  Yohe ME
Journal: Am J Med Genet A
Date: 2020 Jan 8
Branches: CGB, OD
PubMed ID: 31913576
PMC ID: not available
Abstract: RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.
Title: Association between coffee drinking and telomere length in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Authors: Steiner B,  Ferrucci LM,  Mirabello L,  Lan Q,  Hu W,  Liao LM,  Savage SA,  De Vivo I,  Hayes RB,  Rajaraman P,  Huang WY,  Freedman ND,  Loftfield E
Journal: PLoS One
Date: 2020
Branches: CGB, MEB, OD, OEEB
PubMed ID: 31914160
PMC ID: PMC6948744
Abstract: Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99-1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71-2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81-2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations.
Title: Why Y? Down-regulation of chromosome Y genes potentially contributes to elevated cancer risk.
Authors: Brown DW,  Machiela MJ
Journal: J Natl Cancer Inst
Date: 2020 Jan 7
Branches: ITEB
PubMed ID: 31945785
PMC ID: not available
Abstract:
Title: Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.
Authors: Kachuri L,  Johansson M,  Rashkin SR,  Graff RE,  Bossé Y,  Manem V,  Caporaso NE,  Landi MT,  Christiani DC,  Vineis P,  Liu G,  Scelo G,  Zaridze D,  Shete SS,  Albanes D,  Aldrich MC,  Tardón A,  Rennert G,  Chen C,  Goodman GE,  Doherty JA,  Bickeböller H,  Field JK,  Davies MP,  Dawn Teare M,  Kiemeney LA,  Bojesen SE,  Haugen A,  Zienolddiny S,  Lam S,  Le Marchand L,  Cheng I,  Schabath MB,  Duell EJ,  Andrew AS,  Manjer J,  Lazarus P,  Arnold S,  McKay JD,  Emami NC,  Warkentin MT,  Brhane Y,  Obeidat M,  Martin RM,  Relton C,  Davey Smith G,  Haycock PC,  Amos CI,  Brennan P,  Witte JS,  Hung RJ
Journal: Nat Commun
Date: 2020 Jan 7
Branches: ITEB, MEB, OEEB
PubMed ID: 31911640
PMC ID: PMC6946810
Abstract: Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
Title: Association of Powder Use in the Genital Area With Risk of Ovarian Cancer.
Authors: O'Brien KM,  Tworoger SS,  Harris HR,  Anderson GL,  Weinberg CR,  Trabert B,  Kaunitz AM,  D'Aloisio AA,  Sandler DP,  Wentzensen N
Journal: JAMA
Date: 2020 Jan 7
Branches: CGB, MEB
PubMed ID: 31910280
PMC ID: not available
Abstract: Importance: The relationship between use of powder in the genital area and ovarian cancer is not established. Positive associations reported in case-control studies have not been confirmed in cohort studies. Objective: To estimate the association between use of powder in the genital area and ovarian cancer using prospective observational data. Design, Setting, and Participants: Data were pooled from 4 large, US-based cohorts: Nurses' Health Study (enrollment 1976; follow-up 1982-2016; n = 81 869), Nurses' Health Study II (enrollment 1989; follow-up 2013-2017; n = 61 261), Sister Study (enrollment 2003-2009; follow-up 2003-2017; n = 40 647), and Women's Health Initiative Observational Study (enrollment 1993-1998; follow-up 1993-2017; n = 73 267). Exposures: Ever, long-term (≥20 years), and frequent (≥1/week) use of powder in the genital area. Main Outcomes and Measures: The primary analysis examined the association between ever use of powder in the genital area and self-reported incident ovarian cancer. Covariate-adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models. Results: The pooled sample included 252 745 women (median age at baseline, 57 years) with 38% self-reporting use of powder in the genital area. Ten percent reported long-term use, and 22% reported frequent use. During a median of 11.2 years of follow-up (3.8 million person-years at risk), 2168 women developed ovarian cancer (58 cases/100 000 person-years). Ovarian cancer incidence was 61 cases/100 000 person-years among ever users and 55 cases/100 000 person-years among never users (estimated risk difference at age 70 years, 0.09% [95% CI, -0.02% to 0.19%]; estimated HR, 1.08 [95% CI, 0.99 to 1.17]). The estimated HR for frequent vs never use was 1.09 (95% CI, 0.97 to 1.23) and for long-term vs never use, the HR was 1.01 (95% CI, 0.82 to 1.25). Subgroup analyses were conducted for 10 variables; the tests for heterogeneity were not statistically significant for any of these comparisons. While the estimated HR for the association between ever use of powder in the genital area and ovarian cancer risk among women with a patent reproductive tract was 1.13 (95% CI, 1.01 to 1.26), the P value for interaction comparing women with vs without patent reproductive tracts was .15. Conclusions and Relevance: In this analysis of pooled data from women in 4 US cohorts, there was not a statistically significant association between use of powder in the genital area and incident ovarian cancer. However, the study may have been underpowered to identify a small increase in risk.
Title: Siah2 control of T-regulatory cells limits anti-tumor immunity.
Authors: Scortegagna M,  Hockemeyer K,  Dolgalev I,  Poźniak J,  Rambow F,  Li Y,  Feng Y,  Tinoco R,  Otero DC,  Zhang T,  Brown K,  Bosenberg M,  Bradley LM,  Marine JC,  Aifantis I,  Ronai ZA
Journal: Nat Commun
Date: 2020 Jan 7
Branches: BB, ITEB, LTG
PubMed ID: 31911617
PMC ID: PMC6946684
Abstract: Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2-/- mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17, Ccl22, and Foxp3. Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2-/- Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2-/- mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy.
Title: Lifestyle factors and risk of myeloproliferative neoplasms in the NIH-AARP diet and health study.
Authors: Podoltsev NA,  Wang X,  Wang R,  Hofmann JN,  Liao LM,  Zeidan AM,  Mesa R,  Ma X
Journal: Int J Cancer
Date: 2020 Jan 6
Branches: MEB, OEEB
PubMed ID: 31904114
PMC ID: not available
Abstract: The etiology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) is largely unknown. We assessed potential associations between lifestyle factors and MPN risk in the NIH-AARP Diet and Health Study. In this prospective cohort with 463,049 participants aged 50-71 years at baseline (1995-1996) and a median follow-up of 15.5 years, we identified 490 MPN cases, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking was not associated with MPN risk in the overall cohort, but analyses stratified by sex suggested that smoking increased the risk of MPN in women (former smoker vs. nonsmokers, HR = 1.43, 95% CI: 1.03-2.00, p = 0.03; current smokers vs. nonsmokers, HR = 1.71, 95% CI: 1.08-2.71, p = 0.02). Coffee consumption was inversely associated with the risk of PV (high vs. low intake, HR = 0.53, 95% CI: 0.33-0.84, p-trend < 0.01), but not the risk of ET or MPN overall. Further analysis revealed an inverse association between the amount of caffeine intake and PV risk (high vs. low intake, HR = 0.55, 95% CI: 0.39-0.79, p-trend < 0.01). While the consumption of caffeinated coffee appeared to confer a protective effect against PV, the consumption of decaffeinated coffee did not. This large prospective study identified smoking as a risk factor for MPN in women and suggests that caffeine intake is associated with a lower risk of PV.
Title: Analysis of DNA methylation in endometrial biopsies to predict risk of endometrial cancer.
Authors: Multinu F,  Chen J,  Madison JD,  Torres M,  Casarin J,  Visscher D,  Shridhar V,  Bakkum-Gamez J,  Sherman M,  Wentzensen N,  Mariani A,  Walther-Antonio M
Journal: Gynecol Oncol
Date: 2020 Jan 2
Branches: CGB
PubMed ID: 31902687
PMC ID: not available
Abstract: OBJECTIVE: To determine whether analysis of methylated DNA in benign endometrial biopsy (EB) specimens is associated with risk of endometrial cancer (EC). METHODS: We identified 23 women with EBs performed at Mayo Clinic diagnosed as normal (n = 14) or hyperplasia (n = 9) and who later developed endometrial cancer after a median interval of 1 year. Cases were matched 1:1 with patients with benign EBs who did not develop EC (controls) by histology of benign EB (normal endometrium vs. endometrial hyperplasia without atypia), date of EB, age at EB, and length of post-biopsy follow-up. DNA extracted from formalin-fixed paraffin-embedded tissues underwent pyrosequencing to determine percent methylation of promoter region CpGs at 26 loci in 4 genes (ADCYAP1, HAND2, MME, RASSF1A) previously reported as methylated in EC. RESULTS: After pathologic review, 23 matched pairs of cases and controls were identified (14 normal, 9 hyperplasia without atypia per group). Among cases, median time from benign EB to EC was 1 year (range 2 days - 9.2 years). We evaluated 26 CpG sites within 4 genes and found a consistent trend of increasing percentage of methylation from control to case to EC for all CpGs. At the gene-level, mean methylation events of ADCYAP1 and HAND2 in cases were significantly higher than control (p = 0.015 and p = 0.021, respectively). Though the other genes did not reach statistical significance, we observed an increased methylation trend among all genes. Area-under-curve (AUC) calculations (predicting future development of EC in the setting of benign EB) for ADCYAP1 and HAND2 were 0.71 (95% CI 0.55-0.88) and 0.83 (95% CI 0.64-1, respectively). CONCLUSIONS: This proof-of-principle study provides evidence that specific methylation patterns in benign EB correlate with future development of EC.