Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Shen, H. and Fridley, B.L. and Song, H.L. and Lawrenson, K. and Cunningham, J.M. and Ramus, S.J. and Cicek, M.S. and Tyrer, J. and Stram, D. and Larson, M.C. and Kobel, M. and Ziogas, A. and Zheng, W. and Yang, H.P. and Wu, A.H. and Wozniak, E.L. and Woo, Y.L. and Winterhoff, B. and Wik, E. and Whittemore, A.S. and Wentzensen, N. and Weber, R.P. and Vitonis, A.F. and Vincent, D. and Vierkant, R.A. and Vergote, I. and Van Den Berg, D. and Van Altena, A.M. and Tworoger, S.S. and Thompson, P.J. and Tessier, D.C. and Terry, K.L. and Teo, S.H. and Templeman, C. and Stram, D.O. and Southey, M.C. and Sieh, W. and Siddiqui, N. and Shvetsov, Y.B. and Shu, X.O. and Shridhar, V. and Wang-Gohrke, S. and Severi, G. and Schwaab, I. and Salvesen, H.B. and Rzepecka, I.K. and Runnebaum, I.B. and Rossing, M.A. and Rodriguez-Rodriguez, L. and Risch, H.A. and Renner, S.P. and Poole, E.M. and Pike, M.C. and Phelan, C.M. and Pelttari, L.M. and Pejovic, T. and Paul, J. and Orlow, I. and Omar, S.Z. and Olson, S.H. and Odunsi, K. and Nickels, S. and Nevanlinna, H. and Ness, R.B. and Narod, S.A. and Nakanishi, T. and Moysich, K.B. and Monteiro, A.N.A. and Moes-Sosnowska, J. and Modugno, F. and Menon, U. and McLaughlin, J.R. and McGuire, V. and Matsuo, K. and Adenan, N.A.M. and Massuger, L.F.A.G. and Lurie, G. and Lundvall, L. and Lubinski, J. and Lissowska, J. and Levine, D.A. and Leminen, A. and Lee, A.W. and Le, N.D. and Lambrechts, S. and Lambrechts, D. and Kupryjanczyk, J. and Krakstad, C. and Konecny, G.E. and Kjaer, S.K. and Kiemeney, L.A. and Kelemen, L.E. and Keeney, G.L. and Karlan, B.Y. and Karevan, R. and Kalli, K.R. and Kajiyama, H. and Ji, B.T. and Jensen, A. and Jakubowska, A. (2013) Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nature Communications, 4. ISSN 2041-1723

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Abstract

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 x 10(-10)) and clear cell (rs11651755 OR = 0.77, P = 1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Item Type: Article
Uncontrolled Keywords: Genome-wide association; clear-cell carcinoma; prostate-cancer
Subjects: R Medicine
R Medicine > RG Gynecology and obstetrics
Divisions: Faculty of Medicine
Depositing User: Ms Haslinda Lahuddin
Date Deposited: 18 Jul 2014 00:29
Last Modified: 18 Jul 2014 00:29
URI: http://eprints.um.edu.my/id/eprint/10828

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