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Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain - 19/08/20

Doi : 10.1016/j.jaad.2020.03.100 
Michael R. Sargen, MD a, , Donato Calista, MD b, David E. Elder, MBChB c, Daniela Massi, MD, PhD d, Emily Y. Chu, MD, PhD e, Míriam Potrony, PhD f, g, Ruth M. Pfeiffer, PhD h, Cristina Carrera, MD, PhD f, g, Paula Aguilera, MD, PhD f, g, Llucia Alos, MD, PhD i, Susana Puig, MD, PhD f, g, Rosalie Elenitsas, MD e, Xiaohong R. Yang, PhD j, Margaret A. Tucker, MD k, Maria Teresa Landi, MD, PhD j, Alisa M. Goldstein, PhD a
a Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 
b Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy 
c Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 
d Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy 
e Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 
f Melanoma Unit, Dermatology Department, Hospital Clínic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain 
g Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain 
h Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 
i Pathology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain 
j Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 
k Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 

Correspondence and reprint requests to: Michael Sargen, MD, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, 9609 Medical Center Dr, Room 6E-542, Rockville, MD 20850.Clinical Genetics BranchDivision of Cancer Epidemiology and Genetics9609 Medical Center DrRoom 6E-542RockvilleMD20850

Abstract

Background

CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.

Objective

We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.

Methods

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.

Results

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.

Limitations

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.

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


Plan


 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.


© 2020  Publié par Elsevier Masson SAS.
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Vol 83 - N° 3

P. 860-869 - septembre 2020 Retour au numéro
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