ERCC2 – Sarcoma Predisposition

Heterozygous germline variants in ERCC2 have been implicated as emerging risk factors for sarcoma. In a cohort of 177 children, adolescents and young adults with soft tissue or bone sarcomas, germline pathogenic/likely pathogenic variants were detected in 38 patients (21.5%), including two unrelated cases harboring ERCC2 GPVs, but without reported family segregation data (PMID:37536918). An international multi-center study of sarcoma predisposition genes similarly noted ERCC2 among several DNA repair genes contributing to sarcoma susceptibility (PMID:27554610). To date, no functional assays have directly assessed the oncogenic role of ERCC2 variants in sarcoma models. Taken together, the evidence supports a Limited gene–disease association under ClinGen criteria, underscoring the need for larger case series, segregation analyses, and mechanistic studies. Key take-home: ERCC2 germline variants may underlie rare sarcoma predisposition, suggesting inclusion in gene panels for early-onset sarcoma.

References

• Cancer discovery • 2016 • Unfurling the Genetic Map of Sarcomas. PMID:27554610
• Journal of medical genetics • 2023 • Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes. PMID:37536918

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