According to results from a cross-sectional study evaluating the prevalence of germline mutations in a large cohort of men with prostate cancer, only 43.8% of the positive genetic variants detected among the group had corresponding recommendations for germline testing from the National Comprehensive Cancer Network (NCCN) guidelines. This study was published online in JAMA Oncology.1

Recent changes to NCCN guidelines have included recommendations for consideration of germline testing of BRCA1/2, ATM, PALB2, and FANCA genes in all men with metastatic, regional, and high-risk disease, independent of family history, and in those with lower-risk disease and a strong family history of prostate cancer.2 In addition, a Gleason score of at least 7 in men with a personal history of prostate cancer has recently been added to the NCCN Hereditary Breast and Ovarian Cancer guidelines as a factor for consideration regarding recommendations for germline BRCA1/2 testing.3

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The purpose of the current study was to evaluate the prevalence of potentially pathogenic germline variants in a large group of men in light of current NCCN guideline recommendations for germline testing in this disease.

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“To our knowledge, this series of multigene germline testing is the largest in a population with prostate cancer,” the authors wrote.

The study included 3607 men with a personal history of prostate cancer who were unselected for family history, age, or disease stage and received germline testing between 2013 and 2018. There were wide variations in the specific genes analyzed for each patient and the particular testing panels used, with the number of genes interrogated ranging from 2 to 80. Nevertheless, 14 specific genes (ie, ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1,MSH2, MSH6, NBN, PMS2, TP53, RAD51D, and PALB2) were tested in 62% of patients.

Positive germline variants were observed in 17.2% of participants overall, with the frequencies of the 10 most commonly altered genes as follows: BRCA2 (4.74%); CHEK2 (2.88%); ATM (2.03%); MUTYH (2.37%); APC (1.28%); BRCA1 (1.25%); HOXB13 (1.12%); MSH2 (0.69%); TP53 (0.66%); and PALB2 (0.56%). More than half of positive variants were in genes not recommended for germline testing by NCCN guidelines.

Neither family history of cancer nor Gleason scores, available for 90% and 43% of patients, respectively, were associated with the detection of positive germline variants.  Interestingly, the percentages of positive germline variants were significantly lower in those with African American (P =.006) or Hispanic (P =.02) ancestry/ethnicity compared with other ethnic groups.

The authors wrote that study limitations included an underrepresentation of certain ethnic groups (eg, African American, Asian, Hispanic) in the study cohort, and fact that  patient Gleason scores and family history were provided by clinicians, rather than collected through a review of medical records.

“Based on these findings, we propose that genetic testing guidelines should be simplified and expanded to include genetic testing of all men diagnosed with prostate cancer similar to guidelines for pancreatic and colorectal cancer,” the authors wrote in conclusion.


  1. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines [published online February 7, 2019]. JAMA Oncol. doi:10.1001/jamaoncol.2018.6760  
  2. National Comprehensive Cancer Guidelines. Prostate Cancer. V4.2018. Accessed February 7, 2019.
  3. National Comprehensive Cancer Guidelines, Genetic/Familial High-risk Assessment for Breast and Ovarian Cancer. V3.2019. Accessed February 7, 2019.