Genetic determinants of prostate cancer predisposition in Ashkenazi Jews

Background: Prostate cancer (PCa) is the most prevalent cancer among men in the European Union, the USA and Israel, with heritability being a key risk factor. Endogamy and kinship are known to increase the likelihood of transmitting genetic mutations associated with various cancers, as seen in populations with high levels of consanguinity, such as Ashkenazi Jews. The Ashkenazi Jewish population, with a history of genetic bottlenecks and selective migrations, has a higher prevalence of inherited mutations that predispose individuals to various diseases including cancer. This article reviews the literature examining the potential effects of founder mutations specific to Ashkenazi Jews, in enhancing the genetic risk of prostate cancer in this population.
Methods: We searched for English-language articles on DNA mutations in Ashkenazi Jewish patients of any age with prostate cancer of any grade, including various study types, using PubMed and other databases with relevant keywords, and confirmed the search was up-to-date as of January 31^st, 2025.
Results: While the overall burden of PCa may not be higher than in European non-Jews, certain founder mutations in Ashkenazi Jews, especially 6174delT in BRCA2, are linked to increased risk and aggressive forms of PCa. Further research is needed to ascertain unequivocally the potential predisposing role of mutations such as 185delAG in BRCA1 or 471delAAAG in RNASEL.
Conclusions: Overall, genetic screening for PCa risk in Ashkenazi Jewish men, particularly within high-endogamy subgroups (Haredim), may be beneficial. Increasing awareness of familial hereditary prostate cancer among Ashkenazi men and healthcare providers is also crucial for early detection and better management of the condition. The complexity of PCa genetics in Ashkenazim, including the influence of multiple low-penetrance mutations, the possible confounding factor of phenocopies, and the need for larger, more diverse studies, underscores the challenges in identifying definitive genetic risk factors. Further studies are awaited investigating in-depth the aggressiveness and response to treatment of PC among Ashkenazi Jews.

https://www.gov.il/BlobFolder/reports/prostate2022/en/files_publications_units_ICDC_prostate2022.pdf

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