Cancer Predisposition

Prostate cancer is one of the most heritable malignancies: it is estimated that ~50% of prostate cancer risk is due to genetic factors. In addition to common polymorphisms that influence cancer predisposition, we have recently determined that rare highly-penetrant cancer predisposition genes are frequently mutated in men with aggressive/advanced prostate cancer. These predisposition genes link prostate cancer with other heritable cancers such as breast and ovarian cancer in the context of BRCA1/2 mutations and colon cancer in the context of mismatch repair gene mutations. Importantly, mutations in these DNA repair genes identify families at risk for cancer and support precision oncology strategies that exploit responses to specific therapeutics such as PARP inhibitors.

Questions and Projects

  • What are the mechanisms by which homology-directed repair defects drive prostate cancer progression?
  • Does BRCA1/2 loss influence AR signaling and responses to AR-targeted therapy?
  • How does resistance to platinum and PARP inhibitor therapy develop?
  • Are there treatment combinations that can effectively eradicate prostate cancers with BRCA1/2 mutations?
  • What are the appropriate screening/early detection approaches for individuals with inherited BRCA1/2 mutations?
  • What influences cancer penetrance in men and women with germline BRCA1/2 mutations? Are there other heritable factors?
graphic showing the distribution of inherited pathogenic DNA repair gene mutations in men with metastatic prostate cancer.
The distribution of inherited pathogenic DNA repair gene mutations in men with metastatic prostate cancer.


  • Cheng HH. Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2015 Dec 23. PMID: 26724258
  • Pritchard CC, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. New England Journal of Medicine. 2016 Aug 4;375(5):443-53. PMID: 27433846
  • Gulati R, et al. Screening men at increased risk for prostate cancer diagnosis: Model estimates of benefits and harms. Cancer Epidemiol Biomarkers Prev. 2016 Oct 14. pii: cebp.0434.2016. PMID: 27742670