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9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

ABSTRACT: BACKGROUND:Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS:To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS:This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS:This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. IMPACT:The findings further support the view that genetic susceptibility varies according to tumor subtype.

SUBMITTER: Warren H

PROVIDER: S-EPMC3772723 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

Warren Helen H Dudbridge Frank F Fletcher Olivia O Orr Nick N Johnson Nichola N Hopper John L JL Apicella Carmel C Southey Melissa C MC Mahmoodi Maryam M Schmidt Marjanka K MK Broeks Annegien A Cornelissen Sten S Braaf Linda M LM Muir Kenneth R KR Lophatananon Artitaya A Chaiwerawattana Arkom A Wiangnon Surapon S Fasching Peter A PA Beckmann Matthias W MW Ekici Arif B AB Schulz-Wendtland Ruediger R Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael M Burwinkel Barbara B Marme Frederik F Schneeweiss Andreas A Sohn Christof C Guénel Pascal P Truong Thérèse T Laurent-Puig Pierre P Mulot Claire C Bojesen Stig E SE Nielsen Sune F SF Flyger Henrik H Nordestgaard Børge G BG Milne Roger L RL Benítez Javier J Arias-Pérez José-Ignacio JI Zamora M Pilar MP Anton-Culver Hoda H Ziogas Argyrios A Bernstein Leslie L Dur Christina Clarke CC Brenner Hermann H Müller Heiko H Arndt Volker V Langheinz Anne A Meindl Alfons A Golatta Michael M Bartram Claus R CR Schmutzler Rita K RK Brauch Hiltrud H Justenhoven Christina C Brüning Thomas T Chang-Claude Jenny J Wang-Gohrke Shan S Eilber Ursula U Dörk Thilo T Schürmann Peter P Bremer Michael M Hillemanns Peter P Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Bogdanova Natalia N Antonenkova Natalia N Rogov Yuriy Y Bermisheva Marina M Prokofyeva Darya D Zinnatullina Guzel G Khusnutdinova Elza E Lindblom Annika A Margolin Sara S Mannermaa Arto A Kosma Veli-Matti VM Hartikainen Jaana M JM Kataja Vesa V Chenevix-Trench Georgia G Beesley Jonathan J Chen Xiaoqing X Lambrechts Diether D Smeets Ann A Paridaens Robert R Weltens Caroline C Flesch-Janys Dieter D Buck Katharina K Behrens Sabine S Peterlongo Paolo P Bernard Loris L Manoukian Siranoush S Radice Paolo P Couch Fergus J FJ Vachon Celine C Wang Xianshu X Olson Janet J Giles Graham G Baglietto Laura L McLean Cariona A CA Severi Gianluca G John Esther M EM Miron Alexander A Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Andrulis Irene L IL Knight Julia A JA Mulligan Anna Marie AM Weerasooriya Nayana N Devilee Peter P Tollenaar Robert A E M RA Martens John W M JW Seynaeve Caroline M CM Hooning Maartje J MJ Hollestelle Antoinette A Jager Agnes A Tilanus-Linthorst Madeleine M A MM Hall Per P Czene Kamila K Liu Jianjun J Li Jingmei J Cox Angela A Cross Simon S SS Brock Ian W IW Reed Malcolm W R MW Pharoah Paul P Blows Fiona M FM Dunning Alison M AM Ghoussaini Maya M Ashworth Alan A Swerdlow Anthony A Jones Michael M Schoemaker Minouk M Easton Douglas F DF Humphreys Manjeet M Wang Qin Q Peto Julian J dos-Santos-Silva Isabel I

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120802 10

<h4>Background</h4>Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).<h4>Methods</h4>To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).<h4>Results</h4>This replication study provides additional strong evidence of an inverse association between rs865686 and breast can ...[more]

PMID: 22859399

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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

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

Publications

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

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