Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.
Hisani N Horne,
Charles C Chung,
Han Zhang,
Kai Yu,
Ludmila Prokunina-Olsson,
Kyriaki Michailidou,
Manjeet K Bolla,
Qin Wang,
Joe Dennis,
John L Hopper,
Melissa C Southey,
Marjanka K Schmidt,
Annegien Broeks,
Kenneth Muir,
Artitaya Lophatananon,
Peter A Fasching,
Matthias W Beckmann,
Olivia Fletcher,
Nichola Johnson,
Elinor J Sawyer,
Ian Tomlinson,
Barbara Burwinkel,
Frederik Marme,
Pascal Guénel,
Thérèse Truong,
Stig E Bojesen,
Henrik Flyger,
Javier Benitez,
Anna González-Neira,
Hoda Anton-Culver,
Susan L Neuhausen,
Hermann Brenner,
Volker Arndt,
Alfons Meindl,
Rita K Schmutzler,
Hiltrud Brauch,
Ute Hamann,
Heli Nevanlinna,
Sofia Khan,
Keitaro Matsuo,
Hiroji Iwata,
Thilo Dörk,
Natalia V Bogdanova,
Annika Lindblom,
Sara Margolin,
Arto Mannermaa,
Veli-Matti Kosma,
Georgia Chenevix-Trench,
,
Anna H Wu,
David Ven den Berg,
Ann Smeets,
Hui Zhao,
Jenny Chang-Claude,
Anja Rudolph,
Paolo Radice,
Monica Barile,
Fergus J Couch,
Celine Vachon,
Graham G Giles,
Roger L Milne,
Christopher A Haiman,
Loic Le Marchand,
Mark S Goldberg,
Soo H Teo,
Nur A M Taib,
Vessela Kristensen,
Anne-Lise Borresen-Dale,
Wei Zheng,
Martha Shrubsole,
Robert Winqvist,
Arja Jukkola-Vuorinen,
Irene L Andrulis,
Julia A Knight,
Peter Devilee,
Caroline Seynaeve,
Montserrat García-Closas,
Kamila Czene,
Hatef Darabi,
Antoinette Hollestelle,
John W M Martens,
Jingmei Li,
Wei Lu,
Xiao-Ou Shu,
Angela Cox,
Simon S Cross,
William Blot,
Qiuyin Cai,
Mitul Shah,
Craig Luccarini,
Caroline Baynes,
Patricia Harrington,
Daehee Kang,
Ji-Yeob Choi,
Mikael Hartman,
Kee Seng Chia,
Maria Kabisch,
Diana Torres,
Anna Jakubowska,
Jan Lubinski,
Suleeporn Sangrajrang,
Paul Brennan,
Susan Slager,
Drakoulis Yannoukakos,
Chen-Yang Shen,
Ming-Feng Hou,
Anthony Swerdlow,
Nick Orr,
Jacques Simard,
Per Hall,
Paul D P Pharoah,
Douglas F Easton,
Stephen J Chanock,
Alison M Dunning,
Jonine D Figueroa
Abstract
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.