Dataset Information

Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

ABSTRACT: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

SUBMITTER: Hein R

PROVIDER: S-EPMC3413660 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Hein Rebecca R Maranian Melanie M Hopper John L JL Kapuscinski Miroslaw K MK Southey Melissa C MC Park Daniel J DJ Schmidt Marjanka K MK Broeks Annegien A Hogervorst Frans B L FB Bueno-de-Mesquita H Bas HB Muir Kenneth R KR Lophatananon Artitaya A Rattanamongkongul Suthee S Puttawibul Puttisak P Fasching Peter A PA Hein Alexander A Ekici Arif B AB Beckmann Matthias W MW Fletcher Olivia O Johnson Nichola N dos Santos Silva Isabel I Peto Julian J Sawyer Elinor E Tomlinson Ian I Kerin Michael M Miller Nicola N Marmee Frederick F Schneeweiss Andreas A Sohn Christof C Burwinkel Barbara B Guénel Pascal P Cordina-Duverger Emilie E Menegaux Florence F Truong Thérèse T Bojesen Stig E SE Nordestgaard Børge G BG Flyger Henrik H Milne Roger L RL Perez Jose Ignacio Arias JI Zamora M Pilar MP Benítez Javier J Anton-Culver Hoda H Ziogas Argyrios A Bernstein Leslie L Clarke Christina A CA Brenner Hermann H Müller Heiko H Arndt Volker V Stegmaier Christa C Rahman Nazneen N Seal Sheila S Turnbull Clare C Renwick Anthony A Meindl Alfons A Schott Sarah S Bartram Claus R CR Schmutzler Rita K RK Brauch Hiltrud H Hamann Ute U Ko Yon-Dschun YD Wang-Gohrke Shan S Dörk Thilo T Schürmann Peter P Karstens Johann H JH Hillemanns Peter P Nevanlinna Heli H Heikkinen Tuomas T Aittomäki Kristiina K Blomqvist Carl C Bogdanova Natalia V NV Zalutsky Iosif V IV Antonenkova Natalia N NN Bermisheva Marina M Prokovieva Darya D Farahtdinova Albina A Khusnutdinova Elza E Lindblom Annika A Margolin Sara S Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana J Chen Xiaoqing X Beesley Jonathan J Lambrechts Diether D Zhao Hui H Neven Patrick P Wildiers Hans H Nickels Stefan S Flesch-Janys Dieter D Radice Paolo P Peterlongo Paolo P Manoukian Siranoush S Barile Monica M Couch Fergus J FJ Olson Janet E JE Wang Xianshu X Fredericksen Zachary Z Giles Graham G GG Baglietto Laura L McLean Catriona A CA Severi Gianluca G Offit Kenneth K Robson Mark M Gaudet Mia M MM Vijai Joseph J Alnæs Grethe Grenaker GG Kristensen Vessela V Børresen-Dale Anne-Lise AL 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 Glendon Gord G Mulligan Anna Marie AM Figueroa Jonine D JD García-Closas Montserrat M Lissowska Jolanta J Sherman Mark E ME Hooning Maartje M Martens John W M JW Seynaeve Caroline C Collée Margriet M Hall Per P Humpreys Keith K Czene Kamila K Liu Jianjun J Cox Angela A Brock Ian W IW Cross Simon S SS Reed Malcolm W R MW Ahmed Shahana S Ghoussaini Maya M Pharoah Paul D P PD Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Jakubowska Anna A Jaworska Katarzyna K Durda Katarzyna K Złowocka Elżbieta E Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Shen Chen-Yang CY Yu Jyh-Cherng JC Hsu Huan-Ming HM Hou Ming-Feng MF Orr Nick N Schoemaker Minouk M Ashworth Alan A Swerdlow Anthony A Trentham-Dietz Amy A Newcomb Polly A PA Titus Linda L Egan Kathleen M KM Chenevix-Trench Georgia G Antoniou Antonis C AC Humphreys Manjeet K MK Morrison Jonathan J Chang-Claude Jenny J Easton Douglas F DF Dunning Alison M AM

PloS one 20120807 8

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collabora ...[more]

PMID: 22879957

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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

Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Publications

Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Similar Datasets

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