Genome-wide germline correlates of the epigenetic landscape of prostate cancer
| Autor: | Michèle Orain, Lawrence E. Heisler, Alexander Gusev, Cindy Q. Yao, Matthew L. Freedman, Takafumi N. Yamaguchi, Ada Wong, Kathleen E. Houlahan, Vincent Huang, Ram Shankar Mani, Paul C. Boutros, Melvin L.K. Chua, Connor Bell, Thomas Kislinger, John Douglas Mcpherson, Lee Timms, Susmita G. Ramanand, Housheng Hansen He, Jiapei Yuan, Alain Bergeron, Hélène Hovington, Julie Livingstone, Mathieu Lupien, Shadrielle Melijah G. Espiritu, Yves Fradet, Mark Pomerantz, Edward P. O’Connor, Valérie Picard, Anamay Shetty, Alex Murison, Bogdan Pasaniuc, Bernard Têtu, Theodorus van der Kwast, Louis Lacombe, Yu Jia Shiah, Michelle Sam, Jeremy Johns, Alexandre Rouette, Michael Fraser, Ankit Sinha, Adrien Foucal, Robert G. Bristow, Musaddeque Ahmed |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
General Medicine Methylation Epigenome Quantitative trait locus Biology medicine.disease medicine.disease_cause General Biochemistry Genetics and Molecular Biology Germline 3. Good health 03 medical and health sciences Prostate cancer 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis DNA methylation Cancer research medicine Epigenetics Carcinogenesis |
| Zdroj: | Nature Medicine. 25:1615-1626 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/s41591-019-0579-z |
| Popis: | 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. Genetic variants in the germ line modulate DNA methylation in tumors and contribute to the aggressiveness of prostate cancer. |
| Databáze: | OpenAIRE |
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