The Germline and Somatic Origins of Prostate Cancer Heterogeneity

Takafumi N Yamaguchi; Kathleen E Houlahan; Helen Zhu; Natalie Kurganovs; Julie Livingstone; Natalie S Fox; Jiapei Yuan; Jocelyn Sietsma Penington; Chol-Hee Jung; Tommer Schwarz; Weerachai Jaratlerdsiri; Job van Riet; Peter Georgeson; Stefano Mangiola; Kodi Taraszka; Robert Lesurf; Jue Jiang; Ken Chow; Lawrence E Heisler; Yu-Jia Shiah; Susmita G Ramanand; Michael J Clarkson; Anne Nguyen; Shadrielle Melijah G Espiritu; Ryan Stuchbery; Richard Jovelin; Vincent Huang; Connor Bell; Edward O'Connor; Patrick J McCoy; Christopher M Lalansingh; Marek Cmero; Adriana Salcedo; Eva K F Chan; Lydia Y Liu; Phillip D Stricker; Vinayak Bhandari; Riana M S Bornman; Dorota H S Sendorek; Andrew Lonie; Stephenie D Prokopec; Michael Fraser; Justin S Peters; Adrien Foucal; Shingai B A Mutambirwa; Lachlan Mcintosh; Michèle Orain; Matthew Wakefield; Valérie Picard; Daniel J Park; Hélène Hovington; Michael Kerger; Alain Bergeron; Veronica Sabelnykova; Ji-Heui Seo; Mark M Pomerantz; Noah Zaitlen; Sebastian M Waszak; Alexander Gusev; Louis Lacombe; Yves Fradet; Andrew Ryan; Amar U Kishan; Martijn P Lolkema; Joachim Weischenfeldt; Bernard Têtu; Anthony J Costello; Vanessa M Hayes; Rayjean J Hung; Housheng H He; John D McPherson; Bogdan Pasaniuc; Theodorus van der Kwast; Anthony T Papenfuss; Matthew L Freedman; Bernard J Pope; Robert G Bristow; Ram S Mani; Niall M Corcoran; Jüri Reimand; Christopher M Hovens; Paul C Boutros

doi:10.1158/2159-8290.CD-23-0882

The Germline and Somatic Origins of Prostate Cancer Heterogeneity

Cancer Discov. 2025 May 2;15(5):988-1017. doi: 10.1158/2159-8290.CD-23-0882.

Authors

Takafumi N Yamaguchi^#^{1

2

3

4}, Kathleen E Houlahan^#^{1

2

3

4

5

6

7}, Helen Zhu^#^{1

5

6

8}, Natalie Kurganovs^#^{1

8

9

10}, Julie Livingstone^#^{1

2

3

4}, Natalie S Fox^#^{1

2

3

4

5}, Jiapei Yuan¹¹, Jocelyn Sietsma Penington¹², Chol-Hee Jung¹³, Tommer Schwarz^{14

15}, Weerachai Jaratlerdsiri¹⁶, Job van Riet¹⁷, Peter Georgeson¹³, Stefano Mangiola^{9

10

12}, Kodi Taraszka¹⁸, Robert Lesurf¹, Jue Jiang¹⁹, Ken Chow^{9

10

20}, Lawrence E Heisler¹, Yu-Jia Shiah¹, Susmita G Ramanand¹¹, Michael J Clarkson^{9

10}, Anne Nguyen^{9

10}, Shadrielle Melijah G Espiritu¹, Ryan Stuchbery^{9

10}, Richard Jovelin¹, Vincent Huang¹, Connor Bell²¹, Edward O'Connor²¹, Patrick J McCoy^{9

10}, Christopher M Lalansingh¹, Marek Cmero^{9

10

12}, Adriana Salcedo^{1

2

3

4

5}, Eva K F Chan^{22

23}, Lydia Y Liu^{1

2

3

4

5

6}, Phillip D Stricker²³, Vinayak Bhandari^{1

5}, Riana M S Bornman²⁴, Dorota H S Sendorek¹, Andrew Lonie¹³, Stephenie D Prokopec¹, Michael Fraser^{1

8}, Justin S Peters^{9

10}, Adrien Foucal¹, Shingai B A Mutambirwa²⁵, Lachlan Mcintosh¹², Michèle Orain²⁶, Matthew Wakefield¹², Valérie Picard²⁷, Daniel J Park¹³, Hélène Hovington²⁷, Michael Kerger⁹, Alain Bergeron²⁷, Veronica Sabelnykova¹, Ji-Heui Seo²¹, Mark M Pomerantz²¹, Noah Zaitlen^{28

29}, Sebastian M Waszak^{30

31}, Alexander Gusev^{32

33

34}, Louis Lacombe²⁷, Yves Fradet²⁷, Andrew Ryan³⁵, Amar U Kishan^{3

36}, Martijn P Lolkema^{18

37}, Joachim Weischenfeldt^{38

39

40}, Bernard Têtu²⁶, Anthony J Costello^{9

10

20}, Vanessa M Hayes^{22

23

24

41

42}, Rayjean J Hung^{43

44}, Housheng H He^{5

8}, John D McPherson^{1

5}, Bogdan Pasaniuc^{3

4

15

29}, Theodorus van der Kwast⁸, Anthony T Papenfuss^{13

45

46

47

48}, Matthew L Freedman^{21

32

49}, Bernard J Pope^{10

13

50

51

52}, Robert G Bristow^{5

8

53}, Ram S Mani^{11

54}, Niall M Corcoran^#^{9

10

20

55

56}, Jüri Reimand^#^{1

5}, Christopher M Hovens^#^{9

10}, Paul C Boutros^#^{2

3

4

5

6

57}

Affiliations

¹ Ontario Institute for Cancer Research, Toronto, Canada.
² Department of Human Genetics, University of California, Los Angeles, Los Angeles, California.
³ Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, California.
⁴ Institute for Precision Health, University of California, Los Angeles, Los Angeles, California.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, Canada.
⁶ Vector Institute, Toronto, Canada.
⁷ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
⁹ Australian Prostate Cancer Research Centre Epworth, Richmond, Australia.
¹⁰ Department of Surgery, The University of Melbourne, Parkville, Australia.
¹¹ Department of Pathology, UT Southwestern Medical Center, Dallas, Texas.
¹² Bioinformatics Division, Walter and Eliza Hall Institute, Parkville, Australia.
¹³ Melbourne Bioinformatics, The University of Melbourne, Melbourne, Australia.
¹⁴ Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.
¹⁵ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California.
¹⁶ Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
¹⁷ Department of Medical Oncology, Erasmus University, Rotterdam, the Netherlands.
¹⁸ Department of Computer Science, University of California, Los Angeles, Los Angeles, California.
¹⁹ Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Darlinghurst, Australia.
²⁰ Division of Urology, Royal Melbourne Hospital, Parkville, Australia.
²¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
²² St Vincent's Clinical School, University of New South Wales, Randwick, Australia.
²³ Department of Urology, St. Vincent's Hospital Sydney, Darlinghurst, Australia.
²⁴ School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa.
²⁵ Department of Urology, Sefako Makgatho Health Science University, Medunsa, South Africa.
²⁶ Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
²⁷ Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
²⁸ Department of Neurology, University of California, Los Angeles, Los Angeles, California.
²⁹ Department of Computational Medicine, University of California, Los Angeles, Los Angeles, California.
³⁰ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
³¹ Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
³² Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
³³ Division of Genetics, Brigham Women's Hospital and Harvard Medical School, Boston, Massachusetts.
³⁴ The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
³⁵ TissuPath Specialist Pathology Services, Mount Waverley, Australia.
³⁶ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
³⁷ Center for Personalized Cancer Treatment, Rotterdam, the Netherlands.
³⁸ Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
³⁹ Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
⁴⁰ Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁴¹ Central Clinical School, University of Sydney, Camperdown, Australia.
⁴² Department of Medical Sciences, University of Limpopo, Mankweng, South Africa.
⁴³ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada.
⁴⁴ Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁴⁵ Department of Medical Biology, University of Melbourne, Parkville, Australia.
⁴⁶ Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia.
⁴⁷ Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Melbourne, Australia.
⁴⁸ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
⁴⁹ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁵⁰ Department of Clinical Pathology, The University of Melbourne, Parkville, Australia.
⁵¹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia.
⁵² Department of Medicine, Monash University, Clayton, Australia.
⁵³ Manchester Cancer Research Centre, Manchester, United Kingdom.
⁵⁴ Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
⁵⁵ Department of Urology, Peninsula Health, Frankston, Australia.
⁵⁶ The Victorian Comprehensive Cancer Centre, Parkville, Australia.
⁵⁷ Department of Urology, University of California, Los Angeles, Los Angeles, California.

^# Contributed equally.

Abstract

This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.

MeSH terms

Genetic Heterogeneity*
Germ-Line Mutation*
Humans
Male
Mutation
Polymorphism, Single Nucleotide
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology

Abstract

MeSH terms

Grants and funding