CDKN2A – Melanoma-Pancreatic Cancer Syndrome

CDKN2A germline mutations exhibit autosomal dominant inheritance and are a well‐established cause of familial atypical multiple‐mole melanoma and melanoma-pancreatic cancer syndrome ([PMID:35123577]). A novel CDKN2A c.301G>T (p.Gly101Val) variant was identified in a female proband with early‐onset oral squamous cell carcinoma and in her mother, indicating segregation of the mutant allele in one additional affected relative ([PMID:35123577]). No further unrelated cases or larger cohorts have been reported for this specific variant, resulting in a limited case series.

Functional assays across multiple studies demonstrate that missense changes in p16INK4a disrupt its ankyrin repeat structure and impair CDK4 binding and kinase inhibition, consistent with a haploinsufficiency mechanism. Yeast two-hybrid and in vitro kinase assays of p16 mutants show loss or reduction of CDK4 inhibition, corroborating the pathogenicity of destabilizing substitutions ([PMID:7780957]; [PMID:9012842]).

Key Take-home: CDKN2A c.301G>T (p.Gly101Val) is associated with melanoma-pancreatic cancer syndrome but current evidence is limited to a single kindred; functional data support pathogenicity, and testing for CDKN2A mutations should be considered in young patients with head and neck cancers and family history of melanoma and pancreatic neoplasms.

References

• Journal of otolaryngology - head & neck surgery • 2022 • Hereditary oral squamous cell carcinoma associated with CDKN2A germline mutation: a case report. PMID:35123577
• Cancer Research • 1995 • Mutational effects on the p16INK4a tumor suppressor protein. PMID:7780957
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. PMID:9012842

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