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Testing 3,607 men with prostate cancer on a broad gene panel found something inheritable in one in six, and more than a third of them would not have been offered the test under the guidelines then in force.
A cross-sectional study of 3,607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018, unselected for family history, stage of disease or age at diagnosis, at an accredited diagnostic laboratory. Six hundred and twenty men, 17.2%, had a positive result, defined as a pathogenic, likely pathogenic or increased-risk variant, and only 30.7% of those were in BRCA1 or BRCA2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients, 4.5% of those with a positive result. DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of the total population tested. Examination of self-reported family histories indicated that 229 men with positive variants, 37%, would not have been approved for genetic testing under the National Comprehensive Cancer Network genetic and familial breast and ovarian guidelines then applying to prostate cancer.
It is the second half of the argument for unselected germline testing, and it widens the target beyond BRCA: two thirds of the actionable inherited findings in prostate cancer are in other genes, including the mismatch repair genes that open a checkpoint inhibitor route.
Shares CHEK2, Germline BRCA1/2 pathogenic variant (gBRCAm), ATM, DNA damage response & homologous recombination.
Shares Germline BRCA1/2 pathogenic variant (gBRCAm), DNA damage response & homologous recombination, Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining.
Shares MLH1, Germline BRCA1/2 pathogenic variant (gBRCAm), ATM, Germline BRCA mutation (gBRCA).
Shares CHEK2, ATM, JAMA Oncology, Double-strand break repair: HR versus end joining.
Shares CHEK2, Germline BRCA1/2 pathogenic variant (gBRCAm), ATM, Lynch syndrome.
Shares MSH2, MLH1, Lynch syndrome, JAMA Oncology.
Shares MLH1, Germline BRCA1/2 pathogenic variant (gBRCAm), ATM, DNA damage response & homologous recombination.
Shares MSH2, Lynch syndrome, DNA damage response & homologous recombination, Mismatch repair & microsatellite instability.