Genome-wide germline correlates of the epigenetic landscape of prostate cancer

Kathleen E. Houlahan, Yu Jia Shiah, Alexander Gusev, Jiapei Yuan, Musaddeque Ahmed, Anamay Shetty, Susmita G. Ramanand, Cindy Q. Yao, Connor Bell, Edward O’Connor, Vincent Huang, Michael Fraser, Lawrence E. Heisler, Julie Livingstone, Takafumi N. Yamaguchi, Alexandre Rouette, Adrien Foucal, Shadrielle Melijah G. Espiritu, Ankit Sinha, Michelle SamLee Timms, Jeremy Johns, Ada Wong, Alex Murison, Michèle Orain, Valérie Picard, Hélène Hovington, Alain Bergeron, Louis Lacombe, Mathieu Lupien, Yves Fradet, Bernard Têtu, John D. McPherson, Bogdan Pasaniuc, Thomas Kislinger, Melvin L.K. Chua, Mark M. Pomerantz, Theodorus van der Kwast, Matthew L. Freedman, Ram S. Mani, Housheng H. He, Robert G. Bristow, Paul C. Boutros

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor’s epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

Original languageEnglish (US)
Pages (from-to)1615-1626
Number of pages12
JournalNature medicine
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Houlahan, K. E., Shiah, Y. J., Gusev, A., Yuan, J., Ahmed, M., Shetty, A., Ramanand, S. G., Yao, C. Q., Bell, C., O’Connor, E., Huang, V., Fraser, M., Heisler, L. E., Livingstone, J., Yamaguchi, T. N., Rouette, A., Foucal, A., Espiritu, S. M. G., Sinha, A., ... Boutros, P. C. (2019). Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nature medicine, 25(10), 1615-1626. https://doi.org/10.1038/s41591-019-0579-z