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Title: Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.
Authors: Garcia-Closas M,  Hall P,  Nevanlinna H,  Pooley K,  Morrison J,  Richesson DA,  Bojesen SE,  Nordestgaard BG,  Axelsson CK,  Arias JI,  Milne RL,  Ribas G,  González-Neira A,  Benítez J,  Zamora P,  Brauch H,  Justenhoven C,  Hamann U,  Ko YD,  Bruening T,  Haas S,  Dörk T,  Schürmann P,  Hillemanns P,  Bogdanova N,  Bremer M,  Karstens JH,  Fagerholm R,  Aaltonen K,  Aittomäki K,  von Smitten K,  Blomqvist C,  Mannermaa A,  Uusitupa M,  Eskelinen M,  Tengström M,  Kosma VM,  Kataja V,  Chenevix-Trench G,  Spurdle AB,  Beesley J,  Chen X,  Australian Ovarian Cancer Management Group,  Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,  Devilee P,  van Asperen CJ,  Jacobi CE,  Tollenaar RA,  Huijts PE,  Klijn JG,  Chang-Claude J,  Kropp S,  Slanger T,  Flesch-Janys D,  Mutschelknauss E,  Salazar R,  Wang-Gohrke S,  Couch F,  Goode EL,  Olson JE,  Vachon C,  Fredericksen ZS,  Giles GG,  Baglietto L,  Severi G,  Hopper JL,  English DR,  Southey MC,  Haiman CA,  Henderson BE,  Kolonel LN,  Le Marchand L,  Stram DO,  Hunter DJ,  Hankinson SE,  Cox DG,  Tamimi R,  Kraft P,  Sherman ME,  Chanock SJ,  Lissowska J,  Brinton LA,  Peplonska B,  Klijn JG,  Hooning MJ,  Meijers-Heijboer H,  Collee JM,  van den Ouweland A,  Uitterlinden AG,  Liu J,  Lin LY,  Yuqing L,  Humphreys K,  Czene K,  Cox A,  Balasubramanian SP,  Cross SS,  Reed MW,  Blows F,  Driver K,  Dunning A,  Tyrer J,  Ponder BA,  Sangrajrang S,  Brennan P,  McKay J,  Odefrey F,  Gabrieau V,  Sigurdson A,  Doody M,  Struewing JP,  Alexander B,  Easton DF,  Pharoah PD
Journal: PLoS Genet
Date: 2008 Apr
Branches: HREB, LTG, CGB, REB
PubMed ID: 18437204
PMC ID: PMC2291027
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.