Melanoma, ancestralidad y variantes MC1R en la población mestizada uruguaya

Malignant melanoma (MM) is the most dangerous type of skin cancer and the main cause of death produced by skin diseases. In Uruguay, the incidence rate is 3.8/100,000, one of the highest in Latin America. We analyzed the contribution of ancestry and MC1R as a candidate gene for sporadic melanoma in Uruguay. Our objective wasto investigate the possible associations between ancestry and the MC1R gene with sporadic melanoma in the Uruguayan population. To that end, one hundred patients with sporadic MM and 107 controls were recruited. Phenotypic factors and lifestyle were evaluated as risk factors. At the same time, we analyzed fiveancestry informative markers, the MC1R variants (R151, R160 and D294H) and five tag-SNPs. Phototype, atypical nevi, sunburns and recreational exposure were the main risk factors for MM in the Uruguayan population. We confirmed 16q as a candidate region for MM. R151C, and R160W showed an important association with risk of melanoma (OR= 3.85, P= 1 x 10-2; OR= 10.15, P= 7 x 10-3, respectively). Furthermore, three novel MC1R haplotypes from the promoter region were detected,and the two most common haplotypes for the coding region were different to the ones found in Europeans through HapMap. However, MC1R coding region haplotypes revealed a highly similar frequency to that of the Spanish population. Our results showed that the chromosomal 16q region confers susceptibility to MM risk in the Uruguayan population. In addition, the admixed genome structure of the MC1R region could be part of the explanation of melanoma etiology.El melanoma maligno (MM) es uno de los más peligrosos, y la principal causa de muerte producida por tumores de piel. En el Uruguay, la tasa de incidencia es de 3,8/100.000, una de las más altas de América Latina. En este trabajo analizamos la ancestría y el gen candidato MC1R entre los pacientes con MM del Uruguay. Nuestro objetivo fue investigar la posible asociación entre ancestría y el gen MC1R en pacientes con melanoma esporádico en la población uruguaya. Con tal finalidad, se reclutaron 100 pacientes con MM esporádico y 107 controles. Se evaluó el riesgo de factores fenotípicos y de estilo de vida. Además se analizaron cinco marcadores informativos de ancesdencia, variantes del gen MC1R (R151, R160 y D294H) y cinco tagSNPs. El fototipo, los nevos atípicos, quemaduras solares y la exposición recreativa fueron los principales factores de riesgo para MM en la población uruguaya. La región cromosómica 16q es candidata para MM, mientras que R151C y R160W mostraron una importante asociación con el riesgo para MM (OR= 3,85, P= 1 x 10-2; OR= 10,15, P= 7 x 10-3, respectivamente). Por otra parte, se detectaron tres nuevos haplotipos en la región promotora y los dos haplotipos más frecuentes en la región codificante son diferentes a los encontrados en la población europea. Sin embargo, los haplotipos de la región codificante presentan una frecuencia muy similar a las encontradas en la población española. Los resultados muestran que la región cromosómica 16q confiere susceptibilidad al riesgo de MM en la población uruguaya. Por otra parte, la estructura genómica mestizada de la región del MC1R podría explicar la etiología del melanoma

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; doi: http://dx.doi.org/10.13039/501100002322Funder: Radiumhemmets Forskningsfonder; doi: http://dx.doi.org/10.13039/501100007232Funder: Swedish Cancer SocietyFunder: Lunds Universitet Paulsson TrustFunder: CIBER de Enfermedades Raras of the Instituto de Salud Carlos IIIFunder: European Regional Development Fund; doi: http://dx.doi.org/10.13039/501100008530Funder: DiagnopticsFunder: CERCA Programme Generalitat de CatalunyaFunder: Esther Koplowitz Center, Barcelona, SpainFunder: Comision Honoraria de Lucha Contra el Cancer, CSIC, Fundacion Manuel Perez, Montevideo, UruguayBACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families

Clinical, dermoscopic and histopathologic features of genital and extragenital lichen sclerosus

Little is currently known about the dermoscopic patterns of genital and extragenital lichen sclerosus (LS). In order to evaluate and compare the dermoscopic and histopathologic patterns of genital and extragenital lichen sclerosus, a retrospective analysis of clinical, dermoscopic and histopathologic features of genital and extragenital LS, collected between March 2010 and December 2011 at four dermatology clinics in Greece, Italy, Serbia and Uruguay was performed

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families

Birth cohort- specific trends of sun-related behaviors among individuals from an International consortium of melanoma-prone families.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families

Phenotypic and Histopathological Tumor Characteristics According to <i>CDKN2A</i> Mutation Status among Affected Members of Melanoma Families

NCI NIH HHSMedical Research CouncilUniv S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USAFox Chase Canc Ctr, Dept Biostat & Bioinformat, 7701 Burholme Ave, Philadelphia, PA 19111 USAUniv Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USAHop Cochin, AP HP, 27 Rue Faubourg St Jacques, F-75674 Paris, FranceUniv Paris 05, Paris, FranceSheba Med Ctr, Dept Dermatol, Tel Hashomer, IsraelTel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, IsraelLeiden Univ, Med Ctr, Dept Dermatol, Leiden, NetherlandsUniv Genoa, Dept Internal Med & Med Specialties, I-16126 Genoa, ItalyIRCCS AOU San Martino IST Genoa, Genoa, ItalyUniv Leeds, Sect Epidemiol & Biostat, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, EnglandGustave Roussy, Dept Biopathol, Villejuif, FranceGustave Roussy, INSERM, U1186, Villejuif, FranceMaurizio Bufalini Hosp, Dermatol Unit, Cesena, ItalyUniv Utah, Sch Med, Div Genet Epidemiol, Dept Internal Med, Salt Lake City, UT USAIDIBAPS, Hosp Clin, Dept Dermatol, Melanoma Unit, Barcelona, SpainUniv Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, AustraliaUniv Paris Diderot, INSERM, UMR 946, Genet Variat & Human Dis Unit, Paris, FranceUniv Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USAChaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, IsraelUniv Copenhagen Hosp, Dept Clin Genet, DK-2100 Copenhagen, DenmarkNCI, Human Genet Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USAUniv Fed Ciencias Saude Porto Alegre, Porto, RS, BrazilKarolinska Inst, Dept Oncol Pathol, Stockholm, SwedenQIMR Berghofer Med Res Inst, Herston, Qld, AustraliaInst Oncol Ljubljana, Ljubljana, SloveniaUniv Sydney, Westmead Inst Med Res, Ctr Canc Res, Sydney, NSW 2006, AustraliaUniv Sydney, Melanoma Inst Australia, Sydney, NSW 2006, AustraliaUniv Lund Hosp, Dept Surg, S-22185 Lund, SwedenUniv Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, BrazilUniv Republica, Hosp Clin, Catedra Dermatol, Unidad Lesiones Pigmentadas, Montevideo, UruguayOregon Hlth & Sci Univ, Sch Med, Dept Dermatol, Portland, OR USAInst Valenciano Oncol, Dept Dermatol, Valencia, SpainLatvian Biomed Res & Study Ctr, Riga, LatviaUniv Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, BrazilNCI NIH HHS: T32 CA147832NCI NIH HHS: P30 CA016520NCI NIH HHS: R25 CA147832NCI NIH HHS: R01 CA083115MRC: MR/L01629X/1Web of Scienc

Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma

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, CIBER de Enfermedades Raras of the Instituto de Salud Carlos II, Catalan Government, European Commission, Instituto de Salud Carlos III, Consejo Nacional de Ciencia y Tecnologia (CONACYT), Fundacao para o Amparo da Pesquisa do Estado de Sao Paulo (FAPESP), Brazilian Post-Graduation Agency Capes (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior), Comision Honoraria de Lucha Contra el Cancer and Fundacion Manuel Perez, Montevide