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. SawyerIan 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

Research output: Contribution to journalArticle

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). Perallelic 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.

Original languageEnglish
Article numbere0160316
JournalPLoS One
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Horne, H. N., Chung, C. C., Zhang, H., Yu, K., Prokunina-Olsson, L., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Hopper, J. L., Southey, M. C., Schmidt, M. K., Broeks, A., Muir, K., Lophatananon, A., Fasching, P. A., Beckmann, M. W., Fletcher, O., Johnson, N., ... Figueroa, J. D. (2016). Fine-mapping of the 1p11.2 breast cancer susceptibility locus. PLoS One, 11(8), [e0160316]. https://doi.org/10.1371/journal.pone.0160316