Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines

Abstract

IMPORTANCE Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer.OBJECTIVE To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. DESIGN, SETTING, AND PARTICIPANTSCross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. MAIN OUTCOMES AND MEASURESThe frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. RESULTSOf 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in BRCA1/2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. CONCLUSIONS AND RELEVANCECurrent NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.

Population prevalence of individuals meeting criteria for hereditary breast and ovarian cancer testing

“…Guidelines on who should receive genetic counseling and testing have been compiled by expert committees, and are repeatedly revised and expanded. Recent guidelines have suggested more widespread genetic testing given that people with pathogenic variants may not meet referral criteria . A widely used set of criteria are disseminated by the National Comprehensive Cancer Network (NCCN).…”

“…Recent guidelines have suggested more widespread genetic testing given that people with pathogenic variants may not meet referral criteria. 10,11 A widely used set of criteria are disseminated by the National Comprehensive Cancer Network (NCCN). However, there is limited understanding of the prevalence of individuals who meet various testing criteria and thus of the influence of criteria on number of people who might be recommended for testing.…”

Genetic testing for hereditary breast and ovarian cancer and the USPSTF recommendations

“…There are also important implications of the expanded spectrum of BRCA‐associated cancers, which have been recognized over time. While the most common cancers continue to be breast and ovarian cancers, additional cancers have been found to be significantly associated with BRCA gene mutations, specifically prostate and pancreatic cancer, each associated with mutations in several genes, with BRCA2 mutations being the most prevalent . Given this new information, we believe that recommendations for “BRCA‐related Cancer, Genetic Counseling, and Genetic Testing” should consider individuals affected with breast, ovarian, pancreatic, and prostate cancer.…”

“…While the most common cancers continue to be breast and ovarian cancers, additional cancers have been found to be significantly associated with BRCA gene mutations, specifically prostate and pancreatic cancer, each associated with mutations in several genes, with BRCA2 mutations being the most prevalent. [23][24][25][26] Given this new information, we believe that recommendations for "BRCA-related Cancer, Genetic Counseling, and Genetic Testing" should consider individuals affected with breast, ovarian, pancreatic, and prostate cancer. It should be noted that one of the most effective approaches to identifying unaffected individuals is the testing of individuals who have a close relative with cancer and a mutation, so-called Cascade testing.…”

Why is prostate cancer incidence rising in young men?

“…2,3 No analyses of genetics were done in this study but interestingly, when looking at all patients, germline genetic studies indicate that men with DNA repair defects are not more likely to be diagnosed with prostate cancer at an earlier age. 3,4 That said, polygenic risk scores (constructed by aggregating the information from multiple single-nucleotide sequence variants [formerly single-nucleotide polymorphisms]) can markedly alter both the risk of prostate cancer and the age of diagnosis onset. 5 The vast majority of single-nucleotide sequence variants are of unknown function and occur in noncoding regions of the germline DNA.…”