Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02–2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06–3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05–2·44; p=0·04) and Asp294His (2·15, 1·05–4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.
Bibliographical noteFunding Information:
We have received funding for this study from the Society for Pediatric Dermatology (SPD Pilot Project Award 2015 ) and Italian Association for Research on Cancer (AIRC MFAG 11831). PAK has received grants for the Melanoma Susceptibility Study from the National Cancer Institute ( CA75434 , CA80700 , CA092428 ). PG has received funding for the Genoa study from the Italian Association for Research on Cancer ( AIRC IG 15460 ). JL holds a tier 1 Canada Research Chair. The study in the Melanoma Unit, Hospital Clínic (Barcelona, Spain) was supported in part by grants from Fondo de Investigaciones Sanitarias (PI 12/00840, PI15/00956, and PI15/00716) and the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III (Madrid, Spain); was co-funded by EU European Regional Development Funds and by the AGAUR 2014_SGR_603 and 2017_SGR_1134 of the Catalan Government (Spain); and was funded by a grant from Fundació La Marató de TV3 (201331–30; Catalonia, Spain), by the European Commission under the 6th Framework Programme (LSHC-CT-2006–018702; GenoMEL), by the CERCA Programme–Generalitat de Catalunya, and by a research grant from the Fundación Científica de la Asociación Española Contra el Cáncer, Spain (GCB15152978SOEN). Part of the work was developed at the building Centro Esther Koplowitz, Barcelona (Spain). M-FA, FD, and BB-dP have received funding from the Hospital Programme for Clinical Research (France, PHRC 2007 AOM 07–195NI 07004). We thank the medical doctors who included some of the patients of this study. We wish to acknowledge the work of Gustave Roussy Biobank (BB-0033–00074) in providing DNA resources.
© 2019 Elsevier Ltd