Identifying Rare Germline Variants Associated with Metastatic Prostate Cancer Through an Extreme Phenotype Study

Yen-Yi Lin ^1,2, Hamideh Sharifi Noghabi ^1,2, Stanislav Volik ¹

¹Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
²These authors are joint first authors.
³Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
⁴Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
⁵Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁶Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
⁷Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, USA.
⁸Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
⁹The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.
¹⁰Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
¹¹The Institute of Cancer Research, London, UK.
¹²Norwich Medical School, University of East Anglia, Norwich, UK.
¹³The Royal Marsden NHS Foundation Trust, London, UK.
¹⁴Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA.
¹⁵Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁶Hexamer Therapeutics, Pullman, WA, USA.
¹⁷Rural Coordination Center of British Columbia, Vancouver, British Columbia, Canada.
¹⁸Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹St. Paul's Hospital, Vancouver, British Columbia, Canada.
²⁰Department of Experimental Therapeutics, BC Cancer, Vancouver, British Columbia, Canada.
²¹Department of Molecular Oncology, BC Cancer, Vancouver, British Columbia, Canada.
²²Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
²³Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
²⁴School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
²⁵Manchester Cancer Research Centre, University of Manchester, Manchester, UK.
²⁶Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²⁷British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
²⁸These authors are joint last authors.

⁰Vancouver Prostate Centre, Vancouver, British Columbia, Canada.

Medrxiv : the Preprint Server for Health Sciences +

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May 9, 2025

View abstract on PubMed

Summary

Rare germline variants in DNA Damage Repair genes are linked to metastatic prostate cancer (mPCa) risk. Identifying these variants may help stratify patients for aggressive treatment.

Area Of Science

Genetics and Genomics
Cancer Biology
Molecular Oncology

Background

Prostate cancer (PCa) research has focused on germline variants and predisposition.
Limited understanding exists on how heritable factors influence PCa progression and metastasis.

Purpose Of The Study

Identify rare germline variants associated with metastatic PCa (mPCa) risk.
Provide functional validation for identified variants.

Main Methods

Exome sequencing of extreme phenotype cohort (EPC) patients with high-grade PCa.
Analysis of germline variants with minor allelic frequencies ≤ 2%.
Validation in independent PCa cohorts and functional engineering of candidate variants.

Main Results

Germline nonsynonymous rare variants (gnsRVs) in DNA Damage Repair (DDR) genes were enriched in mPCa patients (p=4.57e-06).
<i>KDM6B</i> K973Q and <i>BRCA2</i> I1962T variants showed functional significance and therapeutic implications.
Six EPC variants related to DNA repair or epigenetics altered enzymatic activity.

Conclusions

Extreme phenotype cohorts and rare variant analysis advance understanding of germline-tumor interactions in PCa.
Identified germline variants enriched in mPCa patients, with one conferring a metastatic phenotype.
Germline testing at diagnosis may improve PCa treatment stratification.