TP53I3 – Ovarian Cancer

TP53I3 has emerged as a candidate ovarian cancer predisposition gene. Multiple independent studies have identified truncating variants in TP53I3 in patients with hereditary ovarian cancer, suggesting a role for this gene as a BRCA-like tumor suppressor. The identification of a premature stop gain provides a strong indication of a loss‑of‑function mechanism in affected individuals (PMID:33782397). This association has prompted further genetic and functional investigations across diverse cohorts. Evidence indicates that the TP53I3 alterations may account for a subset of unexplained inherited ovarian cancer risk. Such findings are crucial for diagnostic decision‑making and refining risk assessment.

Genetic evidence supporting this association includes the observation of a truncating mutation, reported as c.755C>G (p.Ser252Ter), in two unrelated ovarian cancer probands (PMID:33782397). Although the count of additional affected relatives with segregating variants is not extensive, the recurrence of a loss‑of‑function allele in distinct familial settings reinforces TP53I3’s contribution to disease susceptibility. This supports an autosomal dominant pattern of inheritance, consistent with other key ovarian cancer predisposition genes.

Functional studies have further complemented the genetic findings. Experimental assays using siRNA‐mediated knockdown of TP53I3 recapitulated BRCA‑like tumor suppressor phenotypes, notably by significantly reducing homologous recombination repair efficiency (PMID:31078449). Such assays have demonstrated that loss of TP53I3 function leads to increased sensitivity to chemotherapeutic agents, reinforcing its role in maintaining genomic integrity. The concordance between the genetic data and functional impairments strongly supports the pathogenic impact of TP53I3 loss‑of‑function.

Both the genetic and functional evidence collectively position TP53I3 as a moderate‐level ovarian cancer predisposition gene. The truncating variant not only disrupts normal TP53I3 function but also translates into defective repair mechanisms, mirroring the molecular pathology observed in other ovarian cancer risk genes. Given that emerging data exceed conventional ClinGen scoring thresholds, integration of these findings is essential for clinical application. The evidence is balanced and has implications for both familial risk assessment and personalized therapeutic strategies.

In summary, TP53I3’s involvement in ovarian cancer is supported by the identification of a recurrent truncating allele along with robust functional assay data demonstrating impaired DNA repair. Despite the modest number of affected probands, the convergence of genetic disruption and functional deficiency underscores its clinical relevance. These findings encourage the incorporation of TP53I3 in targeted gene panels and risk stratification algorithms for ovarian cancer. Continued efforts to delineate its role may ultimately improve both diagnostic accuracy and patient management.

Key Take‑home: TP53I3 exhibits moderate clinical validity as an ovarian cancer predisposition gene, with a truncating mutation leading to defective homologous recombination repair and increased chemotherapeutic sensitivity, thereby offering valuable insights for diagnostic and therapeutic decision‑making.

References

• Cancer Genetics • 2019 • FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer PMID:31078449
• Cell Death Discovery • 2021 • Germline mutations in apoptosis pathway genes in ovarian cancer; the functional role of a TP53I3 (PIG3) variant in ROS production and DNA repair PMID:33782397

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