Dataset Information

Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

ABSTRACT: A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

SUBMITTER: Figueroa JD

PROVIDER: S-EPMC3209823 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

Figueroa Jonine D JD Garcia-Closas Montserrat M Humphreys Manjeet M Platte Radka R Hopper John L JL Southey Melissa C MC Apicella Carmel C Hammet Fleur F Schmidt Marjanka K MK Broeks Annegien A Tollenaar Rob A E M RA Van't Veer Laura J LJ Fasching Peter A PA Beckmann Matthias W MW Ekici Arif B AB Strick Reiner R Peto Julian J dos Santos Silva Isabel I Fletcher Olivia O Johnson Nichola N Sawyer Elinor E Tomlinson Ian I Kerin Michael M Burwinkel Barbara B Marme Federik F Schneeweiss Andreas A Sohn Christof C Bojesen Stig S Flyger Henrik H Nordestgaard Børge G BG Benítez Javier J Milne Roger L RL Ignacio Arias Jose J Zamora M Pilar MP Brenner Hermann H Müller Heiko H Arndt Volker V Rahman Nazneen N Turnbull Clare C Seal Sheila S Renwick Anthony A Brauch Hiltrud H Justenhoven Christina C Brüning Thomas T Chang-Claude Jenny J Hein Rebecca R Wang-Gohrke Shan S Dörk Thilo T Schürmann Peter P Bremer Michael M Hillemanns Peter P Nevanlinna Heli H Heikkinen Tuomas T Aittomäki Kristiina K Blomqvist Carl C Bogdanova Natalia N Antonenkova Natalia N Rogov Yuri I YI Karstens Johann Hinrich JH Bermisheva Marina M Prokofieva Darya D Gantcev Shamil Hanafievich SH Khusnutdinova Elza E Lindblom Annika A Margolin Sara S Chenevix-Trench Georgia G Beesley Jonathan J Chen Xiaoqing X Mannermaa Arto A Kosma Veli-Matti VM Soini Ylermi Y Kataja Vesa V Lambrechts Diether D Yesilyurt Betül T BT Chrisiaens Marie-Rose MR Peeters Stephanie S Radice Paolo P Peterlongo Paolo P Manoukian Siranoush S Barile Monica M Couch Fergus F Lee Adam M AM Diasio Robert R Wang Xianshu X Giles Graham G GG Severi Gianluca G Baglietto Laura L Maclean Catriona C Offit Ken K Robson Mark M Joseph Vijai V Gaudet Mia M John Esther M EM Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Andrulis Irene I Knight Julia A JA Mulligan Anna Marie AM O'Malley Frances P FP Brinton Louise A LA Sherman Mark E ME Lissowska Jolanta J Chanock Stephen J SJ Hooning Maartje M Martens John W M JW van den Ouweland Ans M W AM Collée J Margriet JM Hall Per P Czene Kamila K Cox Angela A Brock Ian W IW Reed Malcolm W R MW Cross Simon S SS Pharoah Paul P Dunning Alison M AM Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Ahn Sei-Hyun SH Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Shen Chen-Yang CY Ding Shian-ling SL Hsu Huan-Ming HM Yu Jyh-Cherng JC Anton-Culver Hoda H Ziogas Argyrios A Ashworth Alan A Swerdlow Anthony A Jones Michael M Orr Nick N Trentham-Dietz Amy A Egan Kathleen K Newcomb Polly P Titus-Ernstoff Linda L Easton Doug D Spurdle Amanda B AB

Human molecular genetics 20110818 23

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or ...[more]

PMID: 21852249

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Project description:Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Dataset Information

Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

Publications

Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.

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