AUA 2020: Genetics in Prostate Cancer: Identification of Inherited Prostate Cancer Risk

( At the virtual American Urological Association 2020 conference webinar, Leonard G. Gomella, MD, began his presentation by noting the May 15 release of the U.S. Food and Drug Administration's approval of the first PARP Inhibitor, rucaparib, for men with metastatic castration-resistant prostate cancer (mCRPC). 

Genetic testing is the centerpiece in cancer management. The Human Genome Project started this movement in 1990 but took 13 years to map the entire human DNA.  Since 2013, there have been many companies working on BRCA genetics because of two important events impacting this field: Angelina Jolie wrote an oped in the New York Times about her decision to have a hysterectomy and bilateral mastectomy because of BRCA-1 & -2 genetics1 and the supreme court ruled that a patent could not be issued for a naturally occurring gene. Dr. Gomella expressed concerns about the recreational genomics companies stepping into the medical world, as some may not be legitimate and if a mistake occurs, the impact could be great. 

Dr. Gomella discussed basic concepts in genomic and genetic testing noting the 3 main applications in genomics:

CancerGenomics BreastOvarian

Modern genetic testing relies on genomics. The following is terminology:

Genetics Genomics Genome

Most studies are on European cohorts and early results show there may not be race differences (Hispanic, AA, southeast Asia) amongst populations. In general, Medicare covers genomic testing if a patient’s relative has cancer or high risk per NCCN guidelines. Only 30% of commercial insurers cover testing. 

Dr. Gomella noted the human genome is a complex area of both normal and mutated genes. If the gene functions normally, does not cause an issue, only when they mutate. Prostate cancer (PCa) are mutated genes, germline mutations, inherited, so can pass it on. 

Genomic testing is performed in tissues and looks for molecular signatures. Tumor sequencing is performed in tissue looking for tumor-specific mutations to inform targeted therapies (clinical trials).  Inherited cancer testing is looking for inherited mutations as these have a significantly higher lifetime cancer risk. This may lead to genetic testing for screening and prevention and to testing of blood relatives.  This type of testing can inform treatment and clinical trials and has the potential to screen and possiblly prevent other at-risk cancers in the patient and/or family. Genomic tissue testing involves sending a piece of the tumor to the lab. Currently, several labs perform genomic testing. Germline genetic testing is obtained from a blood sample or buccal saliva or swab. Next-generation testing is deep sequencing which minimizes errors and is not available in DNA commercial testing. 

As to cancer and inherited risk, Dr. Gomella noted that all cancer is genetic, but not all cancer is hereditary (10-15% cases) as cancer may be due to cell mutations.  Hereditary cancer is due to a single inherited genetic mutation which greatly increases lifetime risk (e.g. BRCA 1, BRCA 2, Lynch syndrome, HOXB13 (inherited PCa)).  BRCA-2 has been studied the most for potential screening and treatment and it is known that men with PCa and BRCA-2 have more aggressive disease. Approximately 15-20% of cases are familial which has some of the same features of hereditary cancer but usually, no detectable mutation is identified. There may be a combined genetic plus environmental risk. But most cases are “sporadic” where the exact cause is not known. 

When looking at PCa, 10-15% are hereditary which is not a cause of cancer but increases the risk.  If the person has inherited mutated genes (BRCA 1/2), they do not cause cancer but increases the person’s risk as these pathogenic genes interact with other genes/environment to increase PCa risk. In these cases, the person is at increased risk for other cancers (breast, ovarian, pancreatic, others) and there is evolving evidence on how best to use these genes for screening and therapy. It is recommended that genomic/genetic germline testing should be performed as the results may have the potential to impact therapeutic options as so-called “actionable genes” may respond to certain treatments, so if identified, may guide treatment.  Mutated genes that are associated with PCa have been identified and most appear to be related to defects in DNA repair mechanisms.  HOXB13 is the gene linked with inherited PCa (grandfather, father, siblings etc).  Germline mutations occur in 11.8% of metastatic and castrate-resistant PCa while 4.6% occur in localized disease. Dr. Gomella said the most important paper on germline mutations in metastatic PCa is by Pritchard et al2 which identified the need to study BRCA‐2 for potential screening and treatment as men with this gene mutation will have more aggressive disease. But more research is needed to identify other PCa genes. 

The relationship between BRCA-1 /2 mutations and PCa is better understood.  Men with these gene mutations are more likely to have aggressive PCa (Gleason > 8 or higher, positive nodes and mets) with poor survival.  They and family members are at increased risk for other hereditary cancers (breast, ovarian, melanoma, pancreatic, Lynch Syndrome, colon, gastric).  Male breast cancer is increased if they have a BRCA 1 / 2 gene mutations. But the percentage of patients who have germline mutations predisposing to PCa remains low.   

Dr. Gomella described his work at the Sidney Kimmel Cancer Center in Philadelphia.  He chaired the 2019 Philadelphia PCa International Consensus Conference which brought together clinicians, basic scientists, and other disciplines to discuss genetic testing for PCa.  In his opinion, urology should become more focused on detailed family history (e.g. breast, ovarian, prostate, melanoma, Lynch Syndrome, male breast cancer, etc.). to inform the need for genetic testing/counseling in men with PCa. He firmly believes in having men diagnosed with PCa meet with a genetic counselor and undergo formal genetic testing. But he recommended caution, as results can have a big impact on the family and may have cause long-term insurance issues.

Presented by: Leonard G. Gomella, MD, Chairman, Department of Urology, Senior Director Clinical Affairs, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 

Written by: Diane Newman, DNP, ANP-BC, Adjunct Professor of Urology in Surgery, Perelman School of Medicine, University of Pennsylvania and Co-Director of the Penn Center for Continence and Pelvic Health, Philadelphia, PA, USA  


  1. Desai S and Jena AB. Do celebrity endorsements matter? Observational study of BRCA gene testing and mastectomy rates after Angelina Jolie's New York Times editorial. BMJ 2016;355 doi:
  2. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144