An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Authors:
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
Asaf Wyszynski Chi-Chen Hong Kristin Lam Kyriaki Michailidou Christian Lytle Song Yao Yali Zhang 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 Julian Peto Isabel Dos-Santos-Silva Elinor J Sawyer Ian Tomlinson Barbara Burwinkel Frederik Marme Pascal Guénel Thérèse Truong Stig E Bojesen Børge G Nordestgaard Anna González-Neira Javier Benitez Susan L Neuhausen Hermann Brenner Aida Karina Dieffenbach Alfons Meindl Rita K Schmutzler Hiltrud Brauch Heli Nevanlinna Sofia Khan Keitaro Matsuo Hidemi Ito Thilo Dörk Natalia V Bogdanova Annika Lindblom Sara Margolin Arto Mannermaa Veli-Matti Kosma Anna H Wu David Van Den Berg Diether Lambrechts Hans Wildiers Jenny Chang-Claude Anja Rudolph Paolo Radice Paolo Peterlongo Fergus J Couch Janet E Olson Graham G Giles Roger L Milne Christopher A Haiman Brian E Henderson Martine Dumont Soo Hwang Teo Tien Y Wong Vessela Kristensen Wei Zheng Jirong Long Robert Winqvist Katri Pylkäs Irene L Andrulis Julia A Knight Peter Devilee Caroline Seynaeve Montserrat García-Closas Daniel Klevebring Kamila Czene Maartje J Hooning Ans M W van den Ouweland Hatef Darabi Xiao-Ou Shu Yu-Tang Gao Angela Cox William Blot Lisa B Signorello Mitul Shah Daehee Kang Ji-Yeob Choi Mikael Hartman Hui Miao Ute Hamann Anna Jakubowska Jan Lubinski Suleeporn Sangrajrang James McKay Amanda E Toland Drakoulis Yannoukakos Chen-Yang Shen Pei-Ei Wu Anthony Swerdlow Nick Orr Jacques Simard Paul D P Pharoah Alison M Dunning Georgia Chenevix-Trench Per Hall Elisa Bandera Chris Amos Christine Ambrosone Douglas F Easton Michael D Cole

Hum Mol Genet 2016 09 11;25(17):3863-3876. Epub 2016 Jul 11.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10) and identify 13 additional linked variants (r>0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10 - 5.6 × 10). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

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http://dx.doi.org/10.1093/hmg/ddw223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216618PMC
September 2016
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5 Citations
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References

(Supplied by CrossRef)
Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice
Tonner et al.
Development 2002

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