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Peer-reviewedCC BY-NC-ND 4.0Prostate Cancer and Prostatic Diseases

Germline genetic risk and prostate cancer–specific mortality in a population-based incident cohort

  • Lucy Lu1
  • Julian Xu1
  • Zhuqing Shi2
  • Valentina Engelmann1
  • Huy Tran2
  • Jun Wei2
  • Annabelle Ashworth2
  • Brandon Cornell1
  • Christopher Pieczonka3
  • William B. Isaacs4
  • S. Lilly Zheng2
  • Brian T. Helfand5,6
3 more authors
  • Jun Luo4
  • Jianfeng Xu2,5,6
  • Jim Lu1
6 affiliations
  1. 1GoPath Diagnostics, LLC, Buffalo Grove, IL USA
  2. 2Program for Genomic Translational Research, Endeavor Health, Evanston, IL USA
  3. 3Associated Medical Professionals of NY (a clinical affiliate of U.S. Urology Partners), Syracuse, NY USA
  4. 4James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD USA
  5. 5Division of Urology, Department of Surgery, Endeavor Health, Evanston, IL USA
  6. 6Division of Urology, Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL USA
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Abstract

Background: Multiple germline variants are associated with prostate cancer (PCa) susceptibility and aggressive features; however, their value for predicting prostate cancer–specific mortality (PCSM) at the time of diagnosis remains uncertain, particularly among men with clinically localized disease.

Methods: We evaluated associations between germline risk factors and PCSM among 14,644 men with incident PCa in the UK Biobank. Associations between PCSM and reported germline risk factors, including 11 genes recommended by the National Comprehensive Cancer Network (NCCN), nine other candidate genes, two common variants [KLK3 (I179T) and HSD3B1 (1245 A > C)], and three polygenic risk scores (PRSs), were tested using Fine–Gray competing-risk models accounting for non–PCa mortality.

Results: During a median follow-up of 6.73 years after diagnosis, 1581 men (10.8%) died from PCa. PVs in three NCCN-recommended DNA damage–repair genes (BRCA2, MSH6, PALB2) were individually associated with increased PCSM and were defined as Tier-1. Aggregated PVs in seven additional NCCN-recommended DDR genes (Tier-2) and the KLK3 I179T variant were also independently associated with PCSM. In contrast, HOXB13, nine other candidate genes, HSD3B1, and all three PRSs were not associated with cumulative PCSM risk. Overall, 14.45% of men carried Tier-1 or Tier-2 PVs and/or KLK3 I179T and experienced significantly earlier PCa-specific mortality. Importantly, associations remained significant among men without metastatic disease at diagnosis.

Conclusions: Reported inherited susceptibility to PCa does not uniformly confer risk of lethal progression. Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease. These findings support consideration of selected germline markers for prognostic risk stratification at diagnosis to inform individualized management decisions.

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Cite

BibTeXRIS
BibTeX
@article{lu2026germline,
  title = {{Germline genetic risk and prostate cancer–specific mortality in a population-based incident cohort}},
  author = {Lucy Lu and Julian Xu and Zhuqing Shi and Valentina Engelmann and Huy Tran and Jun Wei and Annabelle Ashworth and Brandon Cornell and Christopher Pieczonka and William B. Isaacs and S. Lilly Zheng and Brian T. Helfand and Jun Luo and Jianfeng Xu and Jim Lu},
  journal = {Prostate Cancer and Prostatic Diseases},
  year = {2026},
  month = aug,
  doi = {10.1038/s41391-026-01140-5},
  url = {https://doi.org/10.1038/s41391-026-01140-5},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Germline genetic risk and prostate cancer–specific mortality in a population-based incident cohort
AU  - Lucy Lu
AU  - Julian Xu
AU  - Zhuqing Shi
AU  - Valentina Engelmann
AU  - Huy Tran
AU  - Jun Wei
AU  - Annabelle Ashworth
AU  - Brandon Cornell
AU  - Christopher Pieczonka
AU  - William B. Isaacs
AU  - S. Lilly Zheng
AU  - Brian T. Helfand
AU  - Jun Luo
AU  - Jianfeng Xu
AU  - Jim Lu
PY  - 2026
DA  - 2026/08/04
JO  - Prostate Cancer and Prostatic Diseases
DO  - 10.1038/s41391-026-01140-5
UR  - https://doi.org/10.1038/s41391-026-01140-5
AB  - Background: Multiple germline variants are associated with prostate cancer (PCa) susceptibility and aggressive features; however, their value for predicting prostate cancer–specific mortality (PCSM) at the time of diagnosis remains uncertain, particularly among men with clinically localized disease.  Methods: We evaluated associations between germline risk factors and PCSM among 14,644 men with incident PCa in the UK Biobank. Associations between PCSM and reported germline risk factors, including 11 genes recommended by the National Comprehensive Cancer Network (NCCN), nine other candidate genes, two common variants [KLK3 (I179T) and HSD3B1 (1245 A > C)], and three polygenic risk scores (PRSs), were tested using Fine–Gray competing-risk models accounting for non–PCa mortality.  Results: During a median follow-up of 6.73 years after diagnosis, 1581 men (10.8%) died from PCa. PVs in three NCCN-recommended DNA damage–repair genes (BRCA2, MSH6, PALB2) were individually associated with increased PCSM and were defined as Tier-1. Aggregated PVs in seven additional NCCN-recommended DDR genes (Tier-2) and the KLK3 I179T variant were also independently associated with PCSM. In contrast, HOXB13, nine other candidate genes, HSD3B1, and all three PRSs were not associated with cumulative PCSM risk. Overall, 14.45% of men carried Tier-1 or Tier-2 PVs and/or KLK3 I179T and experienced significantly earlier PCa-specific mortality. Importantly, associations remained significant among men without metastatic disease at diagnosis.  Conclusions: Reported inherited susceptibility to PCa does not uniformly confer risk of lethal progression. Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease. These findings support consideration of selected germline markers for prognostic risk stratification at diagnosis to inform individualized management decisions.
SN  - 1365-7852
SN  - 1476-5608
ER  -