MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

Summary Background Germline variants in the melanocortin 1 receptorgene (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 melanomain a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanomato that in adult patients with melanomaand in healthy adult controls. Methods In this retrospective pooled analysis, we used the M-SKIP Project, the Italian MelanomaIntergroup, 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 melanomaat age 20 years or younger, adult patients with sporadic single-primary cutaneous melanomadiagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanomaassociated 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 melanomahad significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanomashowed that MC1R r variants were more prevalent in childhood and adolescent melanomathan in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanomasusceptibility, with a potential clinical relevance for developing early melanomadetection and preventive strategies. Funding SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.