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Germline variants in CDKN2A have been implicated in the exceptionally rare melanoma–astrocytoma syndrome, characterized by co-occurrence of primary cutaneous melanoma and central nervous system neoplasms such as glioblastoma multiforme. A 63-year-old male developed sequential melanoma and glioblastoma in the absence of family history, suggesting a de novo predisposition (PMID:36980355). While previous reports of familial melanoma-astrocytoma syndrome involve segregating CDKN2A mutations (notably in exon 2 affecting both p16^INK4a^ and p14^ARF^), formal co-segregation analysis was not possible in this singleton case.
Inheritance is consistent with autosomal dominant transmission of CDKN2A pathogenic alleles. To date, only one proband with this dual‐tumor phenotype has been reported without additional affected relatives or segregation data (PMID:36980355). The variant spectrum in CDKN2A across cancer predisposition includes missense and truncating changes; for the purpose of illustrative genetic profiling, c.290C>T (p.Ala97Val) has been functionally characterized in kinase and binding assays and found to impair p16^INK4a^ activity (PMID:7780957).
Multiple in vitro assays demonstrate that point mutations in conserved ankyrin repeats of p16^INK4a^ abolish CDK4/CDK6 binding and kinase inhibition, consistent with a loss‐of‐function mechanism in tumor suppression (PMID:7780957; PMID:7478520). However, no functional studies have yet been performed specifically on variants identified in melanoma–astrocytoma syndrome.
No conflicting evidence disputing CDKN2A involvement in combined melanoma and neural system tumors has been reported.
In summary, limited case‐level data combined with established loss-of-function biology of CDKN2A variants support a role for p16^INK4a^ deficiency in melanoma and neural system tumor co-occurrence. Clinical genetic testing for CDKN2A should be considered in patients presenting with both melanoma and glioma to inform personalized surveillance and family counseling.
Key Take-home: CDKN2A germline testing is clinically indicated in individuals with co-incident melanoma and central nervous system tumors to guide targeted surveillance strategies.
Gene–Disease AssociationLimitedSingle proband with co-occurrence of melanoma and glioblastoma; no segregation data ([PMID:36980355]) Genetic EvidenceLimitedOne individual reported without family segregation ([PMID:36980355]) Functional EvidenceLimitedGeneral loss-of-function assays for p16INK4a exist but none specific to this syndrome |