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.
Highlights
Prostate cancer (PrCa) is one of the major causes of morbidity and mortality among men worldwide [1]
Epidemiological studies have revealed that first-degree relatives of a PrCa patient have a two- to three-fold increased risk of developing the disease compared to the general population, and the risk further increases with the number of affected relatives [7]
The proteins encoded by BRCA1 and BRCA2 are known to function in homologous recombination (HR), a vital DNA repair pathway for ensuring genome integrity [49]
Summary
Prostate cancer (PrCa) is one of the major causes of morbidity and mortality among men worldwide [1]. Not consistently, diet and other lifestyle factors, such as smoking and sedentarism, have been pointed out as contributors to an increased risk of PrCa development [9,10,11,12] It is well-recognized that some of the aforementioned risk factors, such as an early onset of the disease and heavy family history, are strong indicators of genetic susceptibility to PrCa development. This susceptibility has been associated with a complex inheritance of both rare variants in moderate- to high-penetrance genes and common genetic alterations in low-risk genes [13,14]. We examine current knowledge regarding the contribution of germline variation to the inherited predisposition to PrCa, and the clinical impact on the management of the disease and patients’ outcome
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