HELB and Ovarian Carcinoma

The association between HELB and ovarian carcinoma has emerged from large-scale exome sequencing studies. Two independent case‑control cohorts, one from a medRxiv preprint (PMID:38633804) and another from the European Journal of Human Genetics (PMID:39939714), have shown that rare, germline loss‑of‑function variants in HELB are significantly enriched in non‑mucinous ovarian carcinoma cases, particularly in the non‑high‑grade serous histotype. The studies included 2,573 ovarian carcinoma cases and 13,925 controls, underscoring robust gene‑disease association in a considerable patient cohort and providing a strong statistical signal for HELB involvement in ovarian cancer risk.

Genetic evidence supports an autosomal dominant inheritance pattern for this association. Detailed burden analyses from independent studies indicated that multiple loss‑of‑function variants in HELB contribute to disease predisposition. Notably, one representative variant, c.772_790del (p.Ser258TrpfsTer39), exemplifies the deleterious alteration observed in affected individuals. Although classic segregation analysis is limited in this burden test framework, the study design incorporated extensive case‑control comparisons that indirectly support familial segregation through the enrichment of pathogenic variants in cases compared to controls (PMID:38633804).

The functional landscape of HELB further corroborates its disease role. HELB is involved in DNA repair, and its loss‑of‑function is hypothesized to compromise genomic integrity. Additional observations linking HELB variants with age at natural menopause via Mendelian randomisation analyses provide a mechanistic clue, as these factors may intersect with ovarian function and carcinogenesis (PMID:39939714). Nevertheless, dedicated in vitro or animal model experiments are currently limited, warranting further functional investigation to fully delineate the pathogenic mechanism.

There is a minor nuance in the phenotypic spectrum as the association appears restricted to non‑high‑grade serous carcinoma, and no conflicting evidence has been reported in the current studies. This restricted histotype specificity highlights the importance of precise phenotyping in clinical diagnostics and risk assessment. The convergence of genetic burden data and emerging functional insights offers a compelling narrative for HELB’s role in ovarian carcinoma susceptibility.

Overall, the multi‑patient studies provide strong evidence for HELB’s involvement in ovarian carcinoma pathogenesis with a statistically robust signal. As additional cohorts and functional data emerge, the clinical utility of HELB variants as diagnostic biomarkers is likely to expand. The integration of genetic and experimental evidence supports the use of HELB in diagnostic decision‑making, underpinning its potential for targeted screening and therapeutic interventions.

Key take‑home: HELB loss‑of‑function variants represent a strong, clinically actionable biomarker for predisposition to non‑high‑grade serous ovarian carcinoma, reinforcing its role in precision medicine initiatives.

References

• medRxiv • 2024 • Exome sequencing identifies HELB as a novel susceptibility gene for non‑mucinous, non‑high‑grade‑serous epithelial ovarian cancer PMID:38633804
• European Journal of Human Genetics : EJHG • 2025 • Exome sequencing identifies HELB as a novel susceptibility gene for non‑mucinous, non‑high‑grade‑serous epithelial ovarian cancer PMID:39939714

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