Bringing Prostate Cancer Germline Genetics into Clinical Practice

Abstract

Purpose: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. Materials and Methods: We searched PubMedÒ for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer NetworkÒ, Bureau of Labor Statistics and National Society of Genetic Counselors websites. Results: A number of germline mutations in DNA damage repair genes (BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study (ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. Conclusions: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.

Acetylation and Deacetylation of DNA Repair Proteins in Cancers

“…Multiple mass spectrum-based studies have identified a diverse number of acetyl-lysine sites on MMR proteins (MSH2, MSH3, MSH6, MLH1, and PMS2) (17,18). Dysregulation of MSH2 has been pointed out to generate genomic instability, resulting in the development of prostate (19), colorectal (20), and hepatic (21) cancers. A previous study found that the levels of MutSα were controlled through MSH2 acetylation in vivo.…”

Clinical Applications of Molecular Biomarkers in Prostate Cancer

“…These findings underscore the need to optimise early detection strategies in men with a high genetic risk-particularly germline mutations in BRCA2-with early screening performed before age 45 or, in patients with a family member diagnosed with cancer, 10 years before the age of diagnosis. In addition, the PSA threshold in these patients should be lowered to 2.5 ng/dL and other biomarkers should be assessed as part of the diagnostic process [66].…”

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

“…Significant factors contributing to the underutilization of genetic testing are likely the lack of clear guidelines regarding how the results should be used to alter management and the shortage of genetic counselors. However, improvements are continuously being made [84][85][86]. Still, there remains a significant amount of work needed to better determine which patients should undergo genetic testing, the timeframe during which testing should be conducted, what techniques should be used, and how the information can be utilized to better serve patients and their families.…”