A polygenic two-hit hypothesis for prostate cancer-Reference-Cited by-同舟云学术

A polygenic two-hit hypothesis for prostate cancer

Published:2023-01-05 Issue:4 Volume:115 Page:468-472
ISSN:0027-8874
Container-title:JNCI: Journal of the National Cancer Institute
language:en
Short-container-title:

Author:

Houlahan Kathleen E¹²³⁴⁵⁶^ORCID,Livingstone Julie¹²⁴⁷,Fox Natalie S¹²³⁴⁵,Kurganovs Natalie⁸⁹¹⁰,Zhu Helen³⁶¹⁰,Sietsma Penington Jocelyn¹¹,Jung Chol-Hee¹²,Yamaguchi Takafumi N¹²⁴⁷,Heisler Lawrence E⁵,Jovelin Richard⁵,Costello Anthony J¹³,Pope Bernard J⁹¹²¹⁴¹⁵,Kishan Amar U²¹⁶,Corcoran Niall M⁸⁹¹³¹⁷¹⁸,Bristow Robert G³¹⁰¹⁹,Waszak Sebastian M²⁰²¹²²,Weischenfeldt Joachim²³²⁴²⁵,He Housheng H³¹⁰,Hung Rayjean J²⁶²⁷,Hovens Christopher M⁸⁹,Boutros Paul C¹²³⁴⁵⁶⁷²⁸

Affiliation:

1. Department of Human Genetics, University of California , Los Angeles, CA, USA

2. Jonsson Comprehensive Cancer Center, University of California , Los Angeles, CA, USA

3. Department of Medical Biophysics, University of Toronto , Toronto, Canada

4. Institute for Precision Health, University of California , Los Angeles, CA, USA

5. Ontario Institute for Cancer Research , Toronto, Canada

6. Vector Institute , Toronto, Canada

7. Department of Urology, University of California , Los Angeles, CA, USA

8. Australian Prostate Cancer Research Centre Epworth , Richmond, VIC, Australia

9. Department of Surgery, The University of Melbourne , Parkville, VIC, Australia

10. Princess Margaret Cancer Centre, University Health Network , Toronto, Canada

11. Bioinformatics Division, Walter and Eliza Hall Institute , Parkville, VIC, Australia

12. Melbourne Bioinformatics, The University of Melbourne , Parkville, VIC, Australia

13. Division of Urology, Royal Melbourne Hospital , Parkville, VIC, Australia

14. Department of Clinical Pathology, The University of Melbourne , Parkville, VIC, Australia

15. Department of Medicine, Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University , Melbourne, VIC, Australia

16. Department of Radiation Oncology, University of California , Los Angeles, CA, USA

17. Department of Urology, Peninsula Health , Frankston, VIC, Australia

18. The Victorian Comprehensive Cancer Centre , Parkville, VIC, Australia

19. Manchester Cancer Research Centre , Manchester, UK

20. Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, and Oslo University Hospital , Oslo, Norway

21. Department of Pediatric Research, Division of Paediatric and Adolescent Medicine, Rikshospitalet, Oslo University Hospital , Oslo, Norway

22. Department of Neurology, University of California , San Francisco, San Francisco, CA, USA

23. Biotech Research and Innovation Centre (BRIC), University of Copenhagen , Copenhagen, Denmark

24. Finsen Laboratory, Rigshospitalet , Copenhagen, Denmark

25. Department of Urology, Charité-Universitätsmedizin Berlin , Berlin, Germany

26. Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto, Canada

27. Epidemiology Division, Dalla Lana School of Public Health, University of Toronto , Toronto, Canada

28. Department of Pharmacology and Toxicology, University of Toronto , Toronto, Canada

Abstract

AbstractProstate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic “two-hit” model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

Funder

Prostate Cancer Canada

Movember Foundation

Terry Fox Research Institute New Investigator Award

Canadian Institutes of Health Research

National Institutes of Health

National Cancer Institute

National Cancer Institute Early Detection Research Network

Informatics Technology for Cancer Research

Terry Fox New Frontiers Program Project Grant

Prostate Cancer Foundation Special Challenge Award

Victorian Health and Medical Research Fellowship