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

1 Citation (Scopus)

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
Externally publishedYes

Fingerprint

Epigenomics
Tumors
Prostatic Neoplasms
Genes
Genome
Methylation
Neoplasms
Quantitative Trait Loci
Biomarkers
Crosstalk
Polymorphism
Triage
Chromatin
Assays
Germ Cells
Prostate
RNA
Carcinogenesis
Tissue
Phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Houlahan, K. E., Shiah, Y. J., Gusev, A., Yuan, J., Ahmed, M., Shetty, 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

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

In: Nature Medicine, Vol. 25, No. 10, 01.10.2019, p. 1615-1626.

Research output: Contribution to journalArticle

Houlahan, KE, Shiah, YJ, Gusev, A, Yuan, J, Ahmed, M, Shetty, A, Ramanand, SG, Yao, CQ, Bell, C, O’Connor, E, Huang, V, Fraser, M, Heisler, LE, Livingstone, J, Yamaguchi, TN, Rouette, A, Foucal, A, Espiritu, SMG, Sinha, A, Sam, M, Timms, L, Johns, J, Wong, A, Murison, A, Orain, M, Picard, V, Hovington, H, Bergeron, A, Lacombe, L, Lupien, M, Fradet, Y, Têtu, B, McPherson, JD, Pasaniuc, B, Kislinger, T, Chua, MLK, Pomerantz, MM, van der Kwast, T, Freedman, ML, Mani, RS, He, HH, Bristow, RG & Boutros, PC 2019, 'Genome-wide germline correlates of the epigenetic landscape of prostate cancer', Nature Medicine, vol. 25, no. 10, pp. 1615-1626. https://doi.org/10.1038/s41591-019-0579-z
Houlahan KE, Shiah YJ, Gusev A, Yuan J, Ahmed M, Shetty A et al. Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nature Medicine. 2019 Oct 1;25(10):1615-1626. https://doi.org/10.1038/s41591-019-0579-z
Houlahan, Kathleen E. ; Shiah, Yu Jia ; Gusev, Alexander ; Yuan, Jiapei ; Ahmed, Musaddeque ; Shetty, Anamay ; Ramanand, Susmita G. ; Yao, Cindy Q. ; Bell, Connor ; O’Connor, Edward ; Huang, Vincent ; Fraser, Michael ; Heisler, Lawrence E. ; Livingstone, Julie ; Yamaguchi, Takafumi N. ; Rouette, Alexandre ; Foucal, Adrien ; Espiritu, Shadrielle Melijah G. ; Sinha, Ankit ; Sam, Michelle ; Timms, Lee ; Johns, Jeremy ; Wong, Ada ; Murison, Alex ; Orain, Michèle ; Picard, Valérie ; Hovington, Hélène ; Bergeron, Alain ; Lacombe, Louis ; Lupien, Mathieu ; Fradet, Yves ; Têtu, Bernard ; McPherson, John D. ; Pasaniuc, Bogdan ; Kislinger, Thomas ; Chua, Melvin L.K. ; Pomerantz, Mark M. ; van der Kwast, Theodorus ; Freedman, Matthew L. ; Mani, Ram S. ; He, Housheng H. ; Bristow, Robert G. ; Boutros, Paul C. / Genome-wide germline correlates of the epigenetic landscape of prostate cancer. In: Nature Medicine. 2019 ; Vol. 25, No. 10. pp. 1615-1626.
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AU - Shetty, Anamay

AU - Ramanand, Susmita G.

AU - Yao, Cindy Q.

AU - Bell, Connor

AU - O’Connor, Edward

AU - Huang, Vincent

AU - Fraser, Michael

AU - Heisler, Lawrence E.

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AU - Foucal, Adrien

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AU - Sinha, Ankit

AU - Sam, Michelle

AU - Timms, Lee

AU - Johns, Jeremy

AU - Wong, Ada

AU - Murison, Alex

AU - Orain, Michèle

AU - Picard, Valérie

AU - Hovington, Hélène

AU - Bergeron, Alain

AU - Lacombe, Louis

AU - Lupien, Mathieu

AU - Fradet, Yves

AU - Têtu, Bernard

AU - McPherson, John D.

AU - Pasaniuc, Bogdan

AU - Kislinger, Thomas

AU - Chua, Melvin L.K.

AU - Pomerantz, Mark M.

AU - van der Kwast, Theodorus

AU - Freedman, Matthew L.

AU - Mani, Ram S.

AU - He, Housheng H.

AU - Bristow, Robert G.

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