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

Simon S. Cross,Frederick Marmee,Vessela N. Kristensen ,Natalia Bogdanova ,Anne Lise Børresen-Dale ,Elżbieta Złowocka,Leslie Bernstein,Marjanka K. Schmidt,Jonathan Beesley,Michael J. Kerin ,Puttisak Puttawibul,Hoda Anton‐Culver ,Zachary S. Fredericksen ,Arto Mannermaa,Sheila Seal,Johann H. Karstens,Christof Sohn,Suleeporn Sangrajrang,Jaana M. Hartikainen ,Linda Titus,Elinor J. Sawyer ,Clare Turnbull,Hans Wildiers,Isabel Dos‐Santos‐Silva ,Douglas F. Easton,Arja Jukkola-Vuorinen,Jenny Chang‐Claude ,Thilo Dörk,Esther M. John,Chen Shen ,James McKay,Christina A. Clarke,Claus R. Bartram,Sarah Schott,Anna Jakubowska,Albina Farahtdinova,Henrik Flyger,Graham G. Giles,Julia A. Knight,Katri Pylkäs,Jianjun Li ,Ming‐Feng Hou ,Antonis C. Antoniou,Jolanta Lissowska,Grethe Grenaker Alnæs,Miroslaw K. Kapuscinski,Javier Benı́tez ,Alexander Miron,Huan Ming Hsu ,Julian Peto,Melissa C. Southey,Jonathan J. Morrison ,Alison M. Dunning,Catriona Mclean ,Peter Schürmann,Natalia Antonenkova ,Irene L. Andrulis,Florence Ménégaux ,Xianshu Wang,Roger L. Milne,M. Pilar Zamora,Olivia Fletcher,Alan Ashworth,Margriet Collée,Kenneth Muir ,Georgia Chenevix-Trench,Argyrios Ziogas,Dong Young Noh ,Keun Young Yoo ,Xiaoqing Chen,Marina Bermisheva,Volker Arndt,Paul Brennan,Maartje J. Hooning ,John W.m. Martens ,Ute Hamann,Jonine D. Figueroa,José Ignacio Arias Peŕez ,Carl Blomqvist,Peter Hillemanns,Anthony Renwick,Emilie Cordina‐Duverger ,Katarzyna Jaworska,Vesa Kataja,Minouk J. Schoemaker ,Katarzyna Durda,Andreas Schneeweiß ,Nichola Johnson,Suthee Rattanamongkongul,Manjeet K. Humphreys,Caroline Seynaeve,Melanie Maranian,Shan Wang-Gohrke,Kathleen M. Egan,Anna Marie Mulligan,Heiko Müller,Frans B.l. Hogervorst ,Kenneth Offit,Janet E. Olson,Peter A. Fasching,Barbara Burwinkel,Paolo Peterlongo,Artitaya Lophatananon,Arif B. Ekici,Mark E. Robson ,Dieter Flesch-Janys,Daniel J. Park,Daehee Kang,Maya Ghoussaini,Fergus J. Couch,Mônica Barile ,Kamila Czene,Paul D.p. Pharoah ,Gord Glendon,Montserrat García‐Closas ,Laura Baglietto,Polly A. Newcomb,Joseph Vijai,Rebecca Hein,Jyh Cherng Yu ,Christa Stegmaier,Patrick Neven,Paolo Radice,Kristiina Aittomäki,Hiltrud Brauch,Ian Tomlinson,Sara Margolin,Nick Orr,Mia M. Gaudet,Per Hall,Valérie Gaborieau ,Annegien Broeks,Diether Lambrechts,Ian W. Brock,Mark E. Sherman,Nicola Miller,Amy Trentham‐Dietz ,Heli Nevanlinna,Robert Winqvist,Gianluca Severi,Tuomas Heikkinen,Shahana Ahmed,Pascal Guénel,Hui Zhao,Nazneen Rahman,Darya Prokovieva,Børge G. Nordestgaard,Э. К. Хуснутдинова ,Annika Lindblom,Alfons Meindl,Keith Humpreys,Rita K. Schmutzler,H. Bas Bueno-de-Mesquit,Stefan Nickels,Alexander Hein,Siranoush Manoukian,Mervi Grip,Yon Ko ,Stig E. Bojesen,Malcolm Reed ,John L. Hopper,Veli Matti Kosma ,Thérèse Truong,Angela Cox,Iosif V. Zalutsky,Hermann Brenner,Anthony Swerdlow,Matthias W. Beckmann

doi:10.1371/journal.pone.0042380

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, pheterogeneity = 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.

Highlights

A genome-wide association study (GWAS) in Chinese women by Zheng et al [1] identified a novel breast cancer susceptibility locus at 6q25.1
Fourteen of the European studies had been designed to oversample cases with a family history of breast cancer, which could have led to an overestimation of the Odds ratio (OR) relative to those expected in a population-based case-control study. Exclusion of these studies does not materially affect the estimated ORs for either single nucleotide polymorphism (SNP). In this large collaborative study of up to 61,689 cases and 58,822 controls, we demonstrate a highly statistically significant association between the A allele of rs2046210 and increased breast cancer risk in women of both Asian and European ancestry, extending the association previously observed in Asian populations
Our study reveals that the G allele of SNP rs12662670 is significantly associated with increased breast cancer risk in both ethnicities

Summary

Introduction

A genome-wide association study (GWAS) in Chinese women by Zheng et al [1] identified a novel breast cancer susceptibility locus at 6q25.1. More recent studies in European women suggested stronger associations with other SNPs in the region: Turnbull et al [3] found the most significantly associated SNP to be rs3757318, which is only weakly correlated with rs2046210 in Europeans (r2 = 0.09 from in HapMap CEU), while Stacey et al [2] suggested that SNPs closer to ESR1 may be more strongly associated. It is as yet unclear whether this difference in breast cancer associated SNPs between Asians and Europeans indicates the presence of a single or multiple causative variant(s) at this locus. If there is only one, it is unlikely to be highly correlated with the best tags identified from either the Asian or European GWAS and could potentially be a common variant with a small effect or a rarer one with a larger effect on breast cancer risk

Objectives

Methods

Results

Conclusion