RNASEH2B – Prostate Cancer

Germline sequencing in a two-stage study identified RNASEH2B as a novel prostate cancer risk gene in 2917 familial or aggressive cases versus 1899 controls (PMID:32800727). In a separate family with multiple glioma and prostate carcinoma cases, the heterozygous RNASEH2B c.529G>A (p.Ala177Thr) variant co-segregated with prostate carcinoma in two affected relatives (father and great-uncle) (PMID:29030706).

Functional studies demonstrate that RNASEH2B p.Ala177Thr carriers exhibit a tumor and peripheral blood type I interferon signature mirroring Aicardi-Goutières syndrome, and that JAK inhibition with Ruxolitinib abrogates this response, supporting an inflammation-driven mechanism in prostate tumorigenesis (PMID:29030706). Integration of genetic association and mechanistic data suggests heterozygous RNASEH2B variants confer moderate risk for prostate cancer; further large-scale studies are needed to refine penetrance estimates. Key take-home: RNASEH2B should be considered in gene panels for familial and aggressive prostate cancer.

References

• European urology • 2021 • Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. PMID:32800727
• Acta neuropathologica • 2017 • Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis. PMID:29030706

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