@article{31186d430b3d48d081be1e9315dc5054,
title = "HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer",
abstract = "Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor.",
keywords = "Cancer, EQTL, HNF1B, Ovarian, Prostate",
author = "Helen Ross-Adams and Stephen Ball and Kate Lawrenson and Silvia Halim and Roslin Russell and Claire Wells and Strand, {Siri H.} and {\O}rntoft, {Torben F.} and Melissa Larson and Sebastian Armasu and Massie, {Charles E.} and Mohammad Asim and Mortensen, {Martin M.} and Michael Borre and Kathryn Woodfine and Warren, {Anne Y.} and Lamb, {Alastair D.} and Jonathan Kay and Hayley Whitaker and Antonio Ramos-Montoya and Adele Murrell and S{\o}rensen, {Karina D.} and Fridley, {Brooke L.} and Goode, {Ellen L.} and Gayther, {Simon A.} and John Masters and Neal, {David E.} and Mills, {Ian G.}",
note = "Funding Information: We are grateful to study volunteers for their participation and to staffat the Wellcome Trust Clinical Research Facility, Addenbrooke's Clinical Research Centre, Cambridge for their help in conducting the study. We acknowledge the support of the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (ProMPT) collaborative (grant code G0500966/75466), which has funded tissue and urine collections in Cambridge, as well as the Human Research Tissue bank, which is supported by the NIHR Cambridge Biomedical Research Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited, and the support of Cancer Research UK Cambridge Institute Genomics and Bioinformatics core facilities. We thank Dr Thorunn Rafnar for helpful discussions and critical review of the manuscript, and Dr Gerhart Ryffel for his kind gift of the HNF1B plasmid. This work was funded by a CRUK program grant awarded to DEN. HR-A and SB were supported by EU Framework Programme 7 grant 202059 (ProMark; http://www.promark-fp7.eu/). The Aarhus Prostate Cancer study is supported by the Danish Strategic Research Council and The Danish Cancer Society. This work was in part supported by the NIH grants R01 CA122443 and P30-CA13083 to ELG and P50-CA136393 to Mayo Clinic SPORE Ovarian Cancer, to ELG. I.G.M. is an Associate Professor at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a visiting scientist and honorary senior visiting research fellow at Cambridge University.",
year = "2016",
doi = "10.18632/oncotarget.12543",
language = "English (US)",
volume = "7",
pages = "74734--74746",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "46",
}