Germline genetics of prostate cancer

Abstract

Background: An important fraction (>/~10%) of men with high-risk, localized prostate cancer and metastatic prostate cancer carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. These can represent known or suspected autosomal dominant cancer predisposition syndromes. Growing evidence suggests that pathogenic variants in key genes involved in homologous recombination and mismatch DNA repair are important in prostate cancer initiation and/or the development of metastases.Aims: Here we provide a comprehensive review regarding individual genes and available literature regarding risks for developing prostate cancer, and discuss current national guidelines for germline genetic testing in the prostate cancer population and treatment implications. Results:The association with prostate cancer risk and treatment implications is best understood for those with germline mutations of BRCA2, with emerging data supporting associations with ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN. Treatment implications in the metastatic castration resistant prostate cancer setting include rucaparib and olaparib, and pembrolizumab with potential clinical trial opportunities in earlier disease settings.Discussion: The data summarized in this review has led to the expansion of national guidelines for germline genetic testing in prostate cancer. We review these guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations with attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.

Personalized Systemic Therapies in Hereditary Cancer Syndromes

“…A meta-analysis including 19 studies revealed that carriers of P/LPVs in ATM have a cumulative lifetime risk of BC of 33% by age 80 years [ 13 ]. Additionally, ATM P/LPVs are also associated with a slight increased risk of OC [ 14 , 15 , 16 ], pancreatic [ 17 ] and prostate [ 18 ] cancer. The cumulative lifetime risk of BC in CHEK2 P/LPVs carriers has been estimated as 28% to 37% [ 19 , 20 ].…”

Implementation of a Telehealth Genetic Testing Station to Deliver Germline Testing for Men With Prostate Cancer

“…The optimal delivery model of PCa genetics care remains unclear. 7,17 Historically, germline testing has been conducted after pretest counseling by GCs. Recently, novel approaches involving oncology staff, with or without GC involvement, that is, hybrid or mainstream models, respectively, have been advocated to increase accessibility and speed.…”

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

“…Examples include one study that found that men with brothers with prostate cancer were significantly more likely to develop any-risk prostate cancer, and another finding that up to 57% of prostate cancer can be attributed to genetic risk factors. 7 In fact, at least 260 germline genetic variants associated with PCa have been identified via whole-genome sequencing — a number that continues to grow as more genetic analyses on more diverse populations are conducted. 8 Germline DNA repair mutations are particularly associated with aggressive disease, metastatic progression, and cancer-specific mortality.…”

“… 8 Germline DNA repair mutations are particularly associated with aggressive disease, metastatic progression, and cancer-specific mortality. 7 , 9 Studies have shown that the percentage of mCRPC patients with germline mutations in these genes range from 8% to 16%. 9–11 …”