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 Sam; Lee 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

doi:10.1038/s41591-019-0579-z

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

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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 language	English
Journal	Nature Medicine
Early online date	7 Oct 2019
DOIs	https://doi.org/10.1038/s41591-019-0579-z
Publication status	Published - Oct 2019

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41591-019-0579-z

Cite this

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. https://doi.org/10.1038/s41591-019-0579-z

@article{7af7d539a99f439eae251396015faf96,

title = "Genome-wide germline correlates of the epigenetic landscape of prostate cancer",

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.",

author = "Houlahan, {Kathleen E} and Yu-Jia Shiah and Alexander Gusev and Jiapei Yuan and Musaddeque Ahmed and Anamay Shetty and Ramanand, {Susmita G} and Yao, {Cindy Q} and Connor Bell and Edward O'Connor and Vincent Huang and Michael Fraser and Heisler, {Lawrence E} and Julie Livingstone and Yamaguchi, {Takafumi N} and Alexandre Rouette and Adrien Foucal and Espiritu, {Shadrielle Melijah G} and Ankit Sinha and Michelle Sam and Lee Timms and Jeremy Johns and Ada Wong and Alex Murison and Mich{\`e}le Orain and Val{\'e}rie Picard and H{\'e}l{\`e}ne Hovington and Alain Bergeron and Louis Lacombe and Mathieu Lupien and Yves Fradet and Bernard T{\^e}tu and McPherson, {John D} and Bogdan Pasaniuc and Thomas Kislinger and Chua, {Melvin L K} and Pomerantz, {Mark M} and {van der Kwast}, Theodorus and Freedman, {Matthew L} and Mani, {Ram S} and He, {Housheng H} and Bristow, {Robert G} and Boutros, {Paul C}",

year = "2019",

month = oct,

doi = "10.1038/s41591-019-0579-z",

language = "English",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Springer Nature",

}

Houlahan, KE, Shiah, Y-J, 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. https://doi.org/10.1038/s41591-019-0579-z

TY - JOUR

T1 - Genome-wide germline correlates of the epigenetic landscape of prostate cancer

AU - Houlahan, Kathleen E

AU - Shiah, Yu-Jia

AU - Gusev, Alexander

AU - Yuan, Jiapei

AU - Ahmed, Musaddeque

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

AU - Livingstone, Julie

AU - Yamaguchi, Takafumi N

AU - Rouette, Alexandre

AU - Foucal, Adrien

AU - Espiritu, Shadrielle Melijah G

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

AU - Boutros, Paul C

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

U2 - 10.1038/s41591-019-0579-z

DO - 10.1038/s41591-019-0579-z

M3 - Article

C2 - 31591588

SN - 1078-8956

JO - Nature Medicine

JF - Nature Medicine

ER -

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

Abstract

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

Fingerprint

Cite this