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

What is the germline mutational landscape in unselected patients with prostate cancer, and do guidelines for genetic
testing  adequately identify patients at risk for aggressive disease? This cross-sectional study of 3607 men with a
personal history of prostate cancer found that 620 (17.2%) had a pathogenic germline variant, of which 229 (37%)
did not qualify (at time of testing) for genetic testing per National Comprehensive Cancer Network recommendations.
National Comprehensive Cancer Network guidelines and Gleason scores are not reliable for stratifying patients
with prostate cancer for the presence or absence of pathogenic germline variants; simplification and expansion
of testing guidelines will improve medical management of these patients.

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.
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.
Cross-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.
The 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.
Of 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. Current 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.
Authors: Piper Nicolosi, PhD; Elisa Ledet, PhD; Shan Yang, PhD; Scott Michalski, MS, LCGC; Brandy Freschi, MS, CGC;
Erin O’Leary, MS, CGC; Edward D. Esplin, MD, PhD; Robert L. Nussbaum, MD; Oliver Sartor, MD.
JAMA Oncol. doi:10.1001/jamaoncol.2018.6760 Published online February 7, 2019.

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