학술논문
Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.
Document Type
article
Author
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
Source
PLoS ONE, Vol 11, Iss 8, p e0160316 (2016)
Subject
Language
English
ISSN
1932-6203
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.