Suchergebnisse

Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P less than 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk. ; The main funding of this project came from the intramural project Papel del estrés oxidativo en el desarrollo de Melanoma Familiar y otras ER comunes con predisposición al desarrollo de neoplasias cutáneas financed by Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund A way to achieve Europe ERDF. The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias Grants PI15/00716 and PI15/00956, of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund A way to achieve Europe ERDF; AGAUR 2017_SGR_1134 of the Catalan Government, Spain; European Commission under the 6th Framework Programme, Contract No. LSHC-CT-2006- 018702 (GenoMEL) and by the European Commission under the 7th Framework Programme, Diagnoptics; The National Cancer Institute (NCI) of the US National Institute of Health (NIH) (CA83115); a grant from Fundació La Marató de TV3 201331- 30, Catalonia, Spain; a grant from Fundación Científica de la Asociación Española Contra el Cáncer GCB15152978SOEN, Spain, and CERCA Programme/Generalitat de Catalunya. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. The UC3M-CIEMAT-CIBERER-IISFJD research is mainly supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2017-86810-R) and from the Community of Madrid (AvanCell-CM S2017/BMD- 3692) which are co-funded with European Regional Development Funds (ERDF). TH was currently recipient of a PhD Fellowship at Radboud University Medical Center in the Netherlands funded by the Dutch Cancer Society (KWF) (10602).

Purpose: CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America. Methods: CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained. Results: Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients. Conclusion: The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first-or second-degree relatives. ; GenoMEL ; National Cancer Institute of the US National Institutes of Health ; Fondo de Investigaciones Sanitarias, Spain ; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain ; Catalan Government, Spain ; European Commission ; Instituto de Salud Carlos III, Spain ; Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico ; Fundacao para o Amparo da Pesquisa do Estado de Sao Paulo (FAPESP), Sao Paulo, Brazil ; Brazilian Post-Graduation Agency Capes (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) ; Comision Honoraria de Lucha Contra el Cancer and Fundacion Manuel Perez, Montevideo, Uruguay ; Hosp Clin & IDIBAPS, Dept Dermatol, Melanoma Unit, Inst Invest Biomed August Pi I Sunyer, Barcelona, Spain ; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain ; Univ Barcelona, Dept Med, Barcelona, Spain ; Consejo Nacl Ciencia & Tecnol CONACYT, Mexico City, DF, Mexico ; Hosp Clin & IDIBAPS, Inst Invest Biomed August Pi I Sunyer, Biochem & Mol Genet Dept, Melanoma Unit, Barcelona, Spain ; Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain ; Univ Cattolica Valencia, Valencia, Spain ; Inst Valenciano Oncol, Mol Biol Unit, Valencia, Spain ; German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany ; Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil ; AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo, Brazil ; Univ Fed Ciencias Saude Porto Alegre, Dept Dermatol, Porto Alegre, RS, Brazil ; Univ Fed Ciencias Saude Porto Alegre, Postgrad Program Pathol, Porto Alegre, RS, Brazil ; Hosp Dr Sotero del Rio, Serv Dermatol, Santiago, Chile ; Hosp San Juan Dios, Serv Dermatol, Santiago, Chile ; Pontificia Univ Catolica Chile, Santiago, Chile ; Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Dept Dermatol, Porto Alegre, RS, Brazil ; Univ Republica, Hosp Clin, Unidad Les Pigmentadas, Catedra Dermatol, Montevideo, Uruguay ; Univ Buenos Aires, Inst Invest Med A Lanari, Buenos Aires, DF, Argentina ; Consultorio Dermatol Drs Cohen Sabban & Cabo, Buenos Aires, DF, Argentina ; Hosp Especialidades Ctr Med Nacl La Raza, Mexico City, DF, Mexico ; Univ Monterrey, Escuela Med, Dept Ciencias Basicas, Monterrey, Mexico ; Univ Autonoma Nuevo Leon, Fac Med, Dept Introducc Clin, Monterrey, Mexico ; Hosp Univ Dr Jose Eleuterio Gonzalez, Serv Dermatol, Monterrey, Mexico ; Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil ; GenoMEL: LSHC-CT-2006-018702 ; National Cancer Institute of the US National Institutes of Health: CA83115 ; Fondo de Investigaciones Sanitarias, Spain: 03/0019 ; Fondo de Investigaciones Sanitarias, Spain: 05/0302 ; Fondo de Investigaciones Sanitarias, Spain: 06/0265 ; Fondo de Investigaciones Sanitarias, Spain: 09/1393 ; Fondo de Investigaciones Sanitarias, Spain: 12/00840 ; Catalan Government, Spain: AGAUR 2014_SGR_603 ; Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico: 152256/158706 ; FAPESP: 2007/04313-2 ; Web of Science