CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.
We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.
We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and non-carriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family.
Histologic slides were evaluated for 290 melanomas (139 from 132 non-carriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in the majority of invasive melanomas from POT1 carriers (10 of 15 [67%], P<.0001 vs. non-carriers). This finding was independently confirmed by three expert melanoma dermatopathologists in 9 of 15 (60%) invasive melanomas. In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from non-carriers.
Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1) CONCLUSION: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to Spitzoid differentiation in melanocytic tumors.

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