Findings from a study recently published in the New England Journal of Medicine suggest that men with advanced prostate cancer may want to consider being tested for inherited gene mutations in order to help guide treatment decision-making and alert family members who may be at risk for a range of cancers.
Prostate cancer is one of the most heritable of human cancers, with 57% of interindividual variation in risk attributed to genetic factors. Additionally, inherited mutations in certain DNA-repair genes are associated with increased risk of lethal prostate cancer. However, while the prevalence of germline mutations in DNA-repair genes is not high enough to warrant routine testing in patients who present with localized prostate cancer, the frequency of these mutations in patients with metastatic disease has not yet been well established.
Therefore, researchers led by Kenneth Offit, MD, Memorial Sloan-Kettering Cancer Center (New York, NY), recruited 692 men diagnosed with metastatic prostate cancer unselected for family history of cancer or age at diagnosis for a study to see how 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. To do so, they isolated the germline DNA and used sequencing assays to assess mutations and compare their prevalence with that found in 499 men with localized disease.
Results of their analysis revealed that 82 men (11.8%) had at least one presumed pathogenic germline mutation in a gene involved in DNA-repair processes. A total of 84 germline mutations presumed to be pathogenic were identified overall (2 men having mutations in 2 separate genes).
A total of 16 different genes in all had mutations, with BRCA2 (37 mutations [44% of total mutations]), ATM (11 [13%]), CHEK2 (10 [12%]), BRCA1 (6 [7%]), RAD51D (3 [4%]), and PALB2 (3 [4%]) occurring most frequently. Additionally, researchers found that the frequency of mutations did not differ based on a family history of prostate cancer or age at diagnosis.
Further analysis also revealed that the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer far exceeded the prevalence of mutations in these same genes (4.6%) observed in the 499 men with localized prostate cancer.
Therefore, researchers concluded that because the frequency of DNA-repair gene mutations is associated with clinical and histological disease, it may be of interest to routinely examine all men with metastatic prostate cancer for germline mutations in these genes.
