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In recent studies, NRDE2 (HGNC:20186) has emerged as a significant contributor to hepatocellular carcinoma (MONDO_0007256). Two independent rare‐variant association studies in Chinese cohorts, one involving 2,750 cases and 4,153 controls (PMID:38697125) and another reporting consistent findings (PMID:38723605), have provided strong evidence for the genetic association between NRDE2 and HCC.
Genetic evidence highlights a rare missense variant, reported as c.1131A>T (p.Asn377Ile), which is implicated in predisposition to HCC. This variant was identified in both studies and demonstrates a statistically significant association with disease risk, supporting an autosomal dominant effect in the affected populations. Although traditional family segregation data are not available, the robust case–control design lends further credence to the observed association.
The studies further detail that the NRDE2-p.Asn377Ile variant plays a crucial role in DNA repair processes. Functional assays revealed that NRDE2 normally promotes homologous recombination repair by binding to casein kinase 2 (CK2) subunits, thereby facilitating MDC1 phosphorylation, a key event in DNA damage response. Loss of NRDE2 function, as observed with the p.Asn377Ile variant, results in impaired repair and sensitizes hepatocellular carcinoma cells to poly(ADP-ribose) polymerase (PARP) inhibitors (PMID:38697125).
Despite the absence of classical familial segregation evidence (with 0 additional affected relatives reported), the convergence of significant genetic association and detailed experimental validation underscores a strong link between NRDE2 dysfunction and hepatocellular carcinoma.
Both genetic and functional studies provide a coherent narrative: NRDE2 variants, particularly the c.1131A>T (p.Asn377Ile) allele, compromise DNA repair pathways and contribute to tumor susceptibility. This integration of multi‐patient genetic data with experimental assays not only bolsters diagnostic decision‑making but also lays the groundwork for potential therapeutic strategies targeting PARP inhibition.
Key take‑home: The comprehensive evidence in multi‐patient cohorts combined with compelling functional results decisively supports the clinical utility of NRDE2 variant screening in managing hepatocellular carcinoma.
Gene–Disease AssociationStrongTwo independent rare-variant association studies in large cohorts (PMID:38697125, PMID:38723605) alongside concordant functional evidence establish a strong link between NRDE2 and hepatocellular carcinoma. Genetic EvidenceStrongThe identification of the NRDE2-p.Asn377Ile variant in significant case-control cohorts supports a robust genetic association with HCC. Functional EvidenceStrongFunctional assays demonstrate that NRDE2 is essential for homologous recombination repair by modulating CK2 activity, with variant-induced loss of function leading to increased PARP inhibitor sensitivity (PMID:38697125). |