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. 2019 Apr 1;5(4):523-528.
doi: 10.1001/jamaoncol.2018.6760.

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

Piper Nicolosi  1 , Elisa Ledet  2 , Shan Yang  1 , Scott Michalski  1 , Brandy Freschi  1 , Erin O'Leary, Edward D Esplin  1 , Robert L Nussbaum  1 , Oliver Sartor  2
Affiliations

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

Piper Nicolosi et al. JAMA Oncol. .

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 participants: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Nicolosi, Yang, Esplin, and Nussbaum and Mr Michalski, Ms Freschi, and Ms O’Leary are employees of Invitae Corporation, a testing laboratory that furnished the diagnostic test results used in this study. Dr Nicolosi reported personal fees from Invitae outside the submitted work. Dr Yang reported other support from Invitae during the conduct of the study. Mr Michalski reported personal fees from Invitae outside the submitted work. Dr Freschi reported personal fees from Invitae outside the submitted work. Dr O’Leary reported being a shareholder of Invitae stock. Dr Esplin reported being a shareholder of Invitae. Dr Nussbaum reported other support from Invitae, personal fees from Pfizer, and personal fees and other support from Genome Medical outside the submitted work. Dr Sartor reported grants from Invitae during the conduct of the study, grants and personal fees from Merck, and grants and personal fees from AstraZeneca outside the submitted work; serves as a consultant for AstraZeneca, Bayer, Bellicum, Bristol-Myers Squibb, Celgene, Dendreon, EMD Serono, Johnson & Johnson, Oncogenex, Pfizer, Sanofi-Aventis, Constellation, Endocyte, Advanced Accelerator Applications, and Bavarian-Nordic; provides research support to Bayer, Endocyte, Innocrin, Johnson & Johnson, Invitae, Sanofi-Aventis, Merck; is a co-chair of the Radiation Therapy Oncology Group Genitourinary Committee; and is a consultant on the Board of Scientific Counselors for National Cancer Institute. No other disclosures were reported.

Figures

Figure.
Figure.. Frequency by Gene of Pathogenic, Likely Pathogenic, and Increased-Risk Allele Variants Detected in This Study
All positive variants detected in a gene were combined and divided by the total number of pathogenic variants detected (n = 674). Mismatch repair (MMR) genes included MLH1, MSH2, MSH6, and PMS2 (no MSH1 variants were detected in this cohort).
See this image and copyright information in PMC

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