Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Chenjie Zeng,Barbara Burwinkel,Saundra S Buys,Cecilia M Dorfling,Jirong Long,Carolyn B Hendricks,Gad Rennert,Keitaro Matsuo,Arnaud Droit,Ana Osorio,Siranoush Manoukian,Julia A Knight,Penny Soucy,Charles Joly Beauparlant,Alice S Whittemore,Robert L Nussbaum,Siddhartha Kar,Per Hall,Marco Montagna,Maria Kabisch,Ian Campbell,Anja Rudolph,Drakoulis Yannoukakos,Mikael Hartman,Fabienne Lesueur,Manuel R Teixeira,Paolo Peterlongo,Peter Hillemanns,Bent Ejlertsen,Graham G Giles,Pascal Guénel,Christian F Singer,Annegien Broeks,Arto Mannermaa,Anthony Swerdlow,Min Hyuk Lee,Peter J Hulick,Alfons Meindl,Volker Arndt,Csilla I Szabo,Minouk J Schoemaker,Caroline Baynes,Thilo Dörk,Joe Dennis,Simon S Cross,Annelie Liljegren,Angela Cox,Miguel De La Hoya,Claudine Isaacs,Norhashimah Hassan,Beth Y Karlan,Henrik Flyger,Michael J Kerin,David E Goldgar,Jingmei Li,Senno Verhoef,Susan M Domchek,Nadine Tung,Suleeporn Sangrajrang,Peter Devilee,Maya Ghoussaini,Silje Nord,Laima Tihomirova,Douglas F Easton,Kerstin Rhiem,Anna H Wu,Stig E Bojesen,Alison M Dunning,Emily Hallberg,Jenny Lester,Gaetana Gambino,Olufunmilayo I Olopade,Judith S Brand,Xingyi Guo,Paul Brennan,Jane Carpenter,Mads Thomassen,Mary B Daly,Jacques Simard,Kamila Czene,Christopher A Haiman,Clare Turnbull,Banu K Arun,Amanda E Toland,Laura Papi,Marc Tischkowitz,Caroline Seynaeve,Sara Margolin,Antoinette Hollestelle,Susan J Ramus,Jaana M Hartikainen,Kenneth Offit,Qiuyin Cai,Catherine M Phelan,Jeffrey N Weitzel,Elinor J Sawyer,Andrew K Godwin,Anna Jakubowska,Irene Konstantopoulou,Peter A Fasching,Carl Blomqvist,Elizabeth J Van Rensburg,Kristiina Aittomäki,Robert Winqvist,Doris Steinemann,Paolo Radice,Fergus J Couch,Peter Schürmann,John L Hopper,Lesley Mcguffog,Shahana Ahmed,Martha J Shrubsole,Rita K Schmutzler,Manjeet K Bolla,Saila Kauppila,Debra Frost,David Ven Den Berg,Annika Lindblom,Sandrine Tchatchou,Susan L Neuhausen,Sue Healey,Bernd Dworniczak,Daehee Kang,Heli Nevanlinna,Esther M John,Daniel C Tessier,Uffe Birk Jensen,Ute Hamann,Artitaya Lophatananon,Peter Kraft,Mark H Greene,Joseph Vijai,Sylvie Mazoyer,Polly A Newcomb,Evgeny N Imyanitov,Kenneth Muir,Irene L Andrulis,Georg Pfeiler,Curtis Olswold,Miriam Dwek,Ava Kwong,Sofia Khan,Nazneen Rahman,Chuen Neng Lee,Thomas Brüning,Roger L Milne,Brita Arver,Bernardo Bonanni,Hermann Brenner,Eitan Friedman,Simona Agata,Ylva Paulsson-Karlsson,Ursula Eilber,Ritu Salani,Qin Wang,William J Blot,Fiona Lalloo,Diether Lambrechts,Georgia Chenevix-Trench,David J Hunter,Marina Bermisheva,Hiltrud Brauch,Daniel Barrowdale,Julian Peto,Kyriaki Michailidou,Steve Ellis,Bernard Peissel,Francesca Damiola,Antonis C Antoniou,Michael Friedlander,Shan Wang-Gohrke,Muhammad Usman Rashid,Katherine L Nathanson,Hidemi Ito,Lothar Haeberle,Mary Beth Terry,Anna Marie Mulligan,Martine Dumont,Zakaria Einbeigi,Yael Laitman,Kim De Leeneer,Andrea Gehrig,Thomas V.o Hansen ,Yu Tang Gao ,Dominique Stoppa‐Lyonnet ,François Bertucci ,Susan L Slager ,Loı̈c Le Marchand ,Alicia Beeghly–Fadiel ,Karoline Kuchenbaecker ,Melissa C Southey ,Florence Ménégaux ,Hoda Anton‐Culver ,Orland Díez ,Э К Хуснутдинова ,Frederik Marmé ,L Phuong ,Natalia Antonenkova ,Paul D.p Pharoah ,Michele M Doody ,Natalia Bogdanova ,Steven N Hart ,Michael E Jones ,Katarzyna Jaworska–Bieniek ,Xiao Ou Shu ,Javier Benı́tez ,Kathleen M Egan ,Stéphanie Peeters ,Isabel Dos‐Santos‐Silva ,Alice J Sigurdson ,Ans M.w Van Den Ouweland ,Montserrat García‐Closas ,Jonine D Figueroa ,Álex Teulé ,Conxi Lázaro ,Jyh Cherng Yu ,Ramūnas Janavičius ,Tien Yin Wong ,Ji Yeob Choi ,Soo Hwang Teo ,Judy E Garber ,Kathleen Claes ,Nadège Presneau ,Aðalgeir Arason ,Anne Lise Børresen-Dale ,Tjoung Won Park-Simon ,Frans B.l Hogervorst ,Jan Lubiński ,Trinidad Caldés ,Edith Oláh ,Chen Shen ,Christine L Clarke ,Marjanka K Schmidt ,Adam N Freeman ,Anna González‐Neira ,Jenny Chang‐Claude ,Zheng Wang

doi:10.1186/s13058-016-0718-0

Abstract

BackgroundMultiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.MethodWe performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.ResultsAnalysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.ConclusionThis study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.

Highlights

Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk
SNPs rs7297051, rs805510 and rs113824616 were associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants
Using forward stepwise selection, we identified two SNPs that were independently associated with breast cancer risk with conditional P < 0.0001, tagging two independent signals (Table 1, Fig. 1)

Summary

Introduction

Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. A previous genome-wide association study (GWAS) identified a common single nucleotide polymorphism (SNP), rs10771399 (termed the index SNP in this paper) at 12p11 to be associated with breast cancer risk in women of European descent [1]. This association, which did not vary by estrogen receptor (ER) status, was one of the most significant associations found for breast cancer risk in Breast cancer 1 (BRCA1) mutation carriers so far, and the association was predominantly found in carriers with ERnegative (ER-(-)) breast cancer [2, 3]. In order to identify additional association signals at the12p11 locus with breast cancer risk, understand the underlying mechanisms and potential causal variants responsible for the association, we conducted a large fine-scale mapping study including data from 55,540 breast cancer cases and 51,168 controls in the Breast Cancer Association Consortium (BCAC) and 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Methods

Results

Discussion

Conclusion