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 noncarriers (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 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers.
Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1).
Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.Le texte complet de cet article est disponible en PDF.
Key words : CDK4, CDKN2A, familial melanoma, melanoma, melanoma pathology, melanoma-prone families, melanoma-susceptibility genes, POT1, Spitz, spitzoid, tumor infiltrating lymphocytes
Abbreviations used : CI, NCI, OR, POT1, MIS, UV
| Drs Landi and Goldstein are cosenior authors.
| Funding sources: This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The research at the Melanoma Unit from the Hospital Clinic of Barcelona is partially funded by grants PI15/00716 and PI15/00956 from Fondo de Investigaciones Sanitarias, Spain; by the grant AC16/00081, integrated in the Plan Estatal I+D+I, IMMUSPHINX (Evaluation of Sphingolipids as Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Melanoma Patients)—TRANSCAN-2; by the Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras of the Instituto de Salud Carlos III (ISCIII), Spain, cofunded by ISCIII-Subdirección General de Evaluación and European Regional Development Fund (ERDF), “A way to build Europe”; Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) 2017_SGR_1134 of the Catalan Government, Spain; by the European Commission under the 6th Framework Programme (Contract No. LSHC-CT-2006-018702, GenoMEL) and 7th Framework Programme (Diagnoptics), and by Centres de Recerca de Catalunya (CERCA) Programme/Generalitat de Catalunya, Spain. Part of the work was developed at the Esther Koplowitz Centre for Biomedical Research, Barcelona.
| Conflicts of interest: None disclosed.
| IRB approval status: Written informed consent was obtained from all participants or their legal guardians before their participation in this study, which was approved by the National Cancer Institute, National Institutes of Health Institutional Review Board, and the ethical committees of each local European institute.