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

Nat Med. 2019 Oct;25(10):1615-1626. doi: 10.1038/s41591-019-0579-z. Epub 2019 Oct 7.

Authors

Kathleen E Houlahan^{1

2

3}, Yu-Jia Shiah¹, Alexander Gusev^{4

5}, Jiapei Yuan⁶, Musaddeque Ahmed⁷, Anamay Shetty^{4

8}, Susmita G Ramanand⁶, Cindy Q Yao¹, Connor Bell⁹, Edward O'Connor⁹, Vincent Huang¹, Michael Fraser¹, Lawrence E Heisler¹, Julie Livingstone¹, Takafumi N Yamaguchi¹, Alexandre Rouette¹, Adrien Foucal¹, Shadrielle Melijah G Espiritu¹, Ankit Sinha^{2

7}, Michelle Sam¹, Lee Timms¹, Jeremy Johns¹, Ada Wong¹, Alex Murison⁷, Michèle Orain¹⁰, Valérie Picard¹¹, Hélène Hovington¹¹, Alain Bergeron¹¹, Louis Lacombe¹¹, Mathieu Lupien^{1

2

7}, Yves Fradet¹¹, Bernard Têtu¹⁰, John D McPherson¹, Bogdan Pasaniuc^{12

13

14}, Thomas Kislinger^{2

7}, Melvin L K Chua^{7

15}, Mark M Pomerantz⁹, Theodorus van der Kwast^{7

16}, Matthew L Freedman^{9

17

18}, Ram S Mani⁶, Housheng H He^{2

7}, Robert G Bristow^{19

20

21

22

23

24

25}, Paul C Boutros^{26

27

28

29

30

31

32

33}

Affiliations

¹ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
³ Vector Institute, Toronto, Ontario, Canada.
⁴ Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁸ University of Cambridge, Cambridge, UK.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Department of Pathology, Centre de recheche du CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹¹ Division of Urology, Centre de recheche du CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹² Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
¹⁶ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
¹⁷ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
¹⁸ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
²⁰ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
²¹ Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
²² Division of Cancer Sciences, Faculty of Biology, Health and Medicine, University of Manchester, Manchester, UK. robert.bristow@manchester.ac.uk.
²³ The Christie NHS Foundation Trust, Manchester, UK. robert.bristow@manchester.ac.uk.
²⁴ Cancer Research UK Manchester Institute, Manchester, UK. robert.bristow@manchester.ac.uk.
²⁵ Manchester Cancer Research Centre, Manchester, UK. robert.bristow@manchester.ac.uk.
²⁶ Ontario Institute for Cancer Research, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
²⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
²⁸ Vector Institute, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
²⁹ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
³⁰ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
³¹ Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
³² Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
³³ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

DNA Methylation / genetics*
Epigenome / genetics*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Genome, Human / genetics
Germ-Line Mutation / genetics*
Humans
Male
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / pathology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology
Proto-Oncogene Proteins c-akt / genetics
Quantitative Trait Loci / genetics

Substances

AKT1 protein, human
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding