PLoS ONE (Jan 2016)

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,
  • kConFab/AOCS Investigators,
  • 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

DOI
https://doi.org/10.1371/journal.pone.0160316
Journal volume & issue
Vol. 11, no. 8
p. e0160316

Abstract

Read online

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.