Research reveals possible predictor of PCa germline mutation

The study of men with prostate cancer also found that the majority of the men with a germline cancer predisposition gene mutation did not meet existing criteria for clinical genetic testing.

Multiple primary cancers in a single individual can suggest the presence of a germline cancer predisposition gene mutation. Now, in a study published online in Cancer (June 28, 2017), researchers report that men with prostate cancer and one or more additional cancers may have a higher chance of harboring a germline cancer predisposition gene mutation compared to the general population of men with prostate cancer.

The study also found that the majority of the men with a germline cancer predisposition gene mutation did not meet existing criteria for clinical genetic testing.

Senior author Kathleen A. Cooney, MD, of the Huntsman Cancer Institute and University of Utah, Salt Lake City, told Urology Times, “It is important to note that we used very stringent criteria for case selection to increase the likelihood of finding germline mutations, including early age of onset for the first cancer (≤55 years), more than two primary cancers, and the presence of rare cancers. Still, we believe that practicing urologists should be aware that men with prostate cancer and one or more additional primary cancers may harbor a germline mutation in a cancer susceptibility gene, and they should consider referring these patients to a cancer genetics clinic for further evaluation when appropriate.”

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The study included 102 men identified from the University of Michigan Prostate Cancer Genetics Project and Cancer Genetics Clinic registry. A certified genetic counselor reviewed each patient’s personal and family histories to determine their eligibility for clinical genetic testing based on criteria from the 2015 guidelines of the National Comprehensive Cancer Network for hereditary breast-ovarian cancer, Li-Fraumeni syndrome, Lynch syndrome, PTEN hamartoma tumor syndrome, or familial adenomatous polyposis. Gene mutational analysis was done using a multigene panel approach.

In this population, melanoma was the most common additional primary cancer and was reported in 33% of the participants. The prostate cancer had a Gleason score ≥7 in 50 men (56.8%) and was clinically aggressive (Gleason score >7, T3b or T4 disease, PSA >15 ng/mL, Gleason score 7 with a PSA >10 ng/mL, or N1 or M1) in 31 men (30.4%).

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A pathogenic or likely pathogenic mutation in a cancer-predisposing gene was found in 11 men (10.8%), with the majority of the variants being in a DNA damage repair pathway gene. Only four (36.4%) of the 11 men met any of the NCCN criteria for clinical genetic testing.

“The identification of pathogenic germline mutations has implications for both targeted treatment of men with prostate cancer and genetic testing and cancer screening strategies of his family members,” Dr. Cooney told Urology Times.

“For example, prostate cancer patients with DNA repair gene mutations have been shown to have better responses to targeted therapies like PARP (poly ADP ribose polymerase) inhibition. Family members may benefit from genetic testing to determine if they also harbor the family’s specific pathogenic mutation. If found to be a carrier, cancer screening started at an earlier age or performed at a greater frequency may improve the chances of early detection.”

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The men found to be mutation carriers were not significantly different from the rest of the study population with respect to age of onset, family history, number of primary malignancies, or presence of metastatic or clinically aggressive disease.

“With a highly selected subset of patients, the results may not extend to the general population. More work is needed to confirm the results in a larger cohort. If confirmed, revisions to the current guidelines for genetic testing in prostate cancer may be warranted,” Dr. Cooney said.

Currently, the authors are using the Utah Population Database to study the personal and family history of cancer in men with prostate cancer.

“The Utah Population Database is an extensive registry, and depending on our findings, we will recruit individuals for additional genetic studies in the future,” Dr. Cooney said.