Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Abstract

Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10–20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.

A Review on the Current Treatment Paradigm in High-Risk Prostate Cancer

“…These studies also highlight the role of personalization in systemic therapy, with expression of specific genes playing a role in response to treatment. A number of genes have been identified to play a critical role in prostate cancer [65], and we will likely see incorporation of new systemic therapy agents in high-risk prostate cancer-often guided by molecular markers-in the years to come. Table S1 summarizes the advantage and disadvantages of different treatment strategies in high-risk prostate cancer.…”

Next-generation sequencing of BRCA1 and BRCA2 genes in Moroccan prostate cancer patients with positive family history

“…Currently, more than 2000 and 2400 distinct germline mutations have been described in BRCA1 and BRCA2 respectively [14]. Previous studies have observed that BRCA1 and BRCA2 pathogenic mutations carriers have 1.8 to 3.8-fold and 2.5 to 8.6-fold increased relative risk of developing PrCa by the age of �65 years old, respectively [15][16][17][18][19].…”

Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

“…The relative risk of HPCa in MMR mutation carriers has been estimated in the interval 2.0–3.7% [ 23 ], even though a previous study reported a nearly five-fold increased risk of HPCa onset in LS men, but without earlier onset or a more aggressive phenotype [ 37 ]. Additionally, studies have also highlighted a considerably higher PCa risk for MSH2 mutation carriers compared to MLH1 and MSH6 [ 38 ].…”

“…Regarding BRCA genes, 64% of the BRCA2 mutations found in HPCa are frameshift, 31% missense and 5% splice. In BRCA1 gene, 63% of the mutations found are missense, 31% frameshift and 6% splice [ 38 ]. Besides, in a study conducted on PCa patients mutated in BRCA1/2 , a more aggressive phenotype was observed [ 30 , 62 ].…”

“…Several studies have evaluated the contribution of BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) founder mutations to PCa risk among Ashkenazi Jewish men. Overall, BRCA2 mutations conferred at least a three-fold elevated risk of high grade PCa, while BRCA1 mutations conferred a lower risk [ 38 , 64 , 65 ].…”