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

Abstract

Background: Germline variants in MC1R may increase risk of childhood/adolescent melanoma, but a clear conclusion is challenging because of the limited number of studies and cases. We evaluated the association of MC1R variants and childhood/adolescent melanoma in a large study comparing the prevalence of MC1R variants of childhood/adolescent melanoma patients to that among adult melanoma cases and unaffected controls. Methods: Phenotypic and genetic data on 233 childhood/adolescent (≤20 years) and 932 adult melanoma patients, and 932 unaffected controls, were gathered through the M-SKIP Project, the Italian Melanoma Intergroup and European centers. We calculated odds ratios (OR) for childhood/adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged ≤18 and ≤14 years. Findings: Children and adolescents had a higher odds of carrying MC1R r variants than adults (OR:1•54; 95%CI:1•02-2•33), also when analysis was restricted to cases ≤18 years (OR:1•80; 95%CI:1•06-3•07). All the investigated variants except R160W showed a higher frequency in childhood/adolescent melanoma compared to adult melanoma, with significant results for V60L (OR:1•60; 95%CI:1•05-2•44) and D294H (OR:2•15; 95%CI:1•05-4•40). Compared to unaffected controls, childhood/adolescent melanoma patients had significantly higher frequencies of any MC1R variants.. Interpretation: Our pooled-analysis of childhood/adolescent patients with MC1R genetic data revealed that MC1R r variants were more prevalent in childhood/adolescent compared to adult melanoma especially in children ≤18 years. Our findings support the role of MC1R in childhood/adolescent melanoma susceptibility with a potential clinical relevance in developing early melanoma detection and preventive strategies.

Fibroblast Growth Factor Receptor Signaling in Skin Cancers

“…Several factors, such as dose of sun exposure, age, gender, fair skin phenotype, and previous keratinocyte skin cancers, are considered as causal factors of initiation and progression of melanoma, with UV-induced damage of DNA as the primary cause of melanoma development [149,150,151]. However, the incidence of melanoma in childhood and at sites that are minimally exposed to the sun are also registered [152,153]. There is hope that genome-wide studies will help to identify the heritable and environmentally-triggered contributors to melanoma risk [153,154,155,156,157].…”

“…However, the incidence of melanoma in childhood and at sites that are minimally exposed to the sun are also registered [152,153]. There is hope that genome-wide studies will help to identify the heritable and environmentally-triggered contributors to melanoma risk [153,154,155,156,157]. Another important issue is to correctly prognose the melanoma progression.…”

The Genetic Germline Background of Single and Multiple Primary Melanomas

“…In this study, we found that MC1R variants were almost equally distributed across both groups of patients, those with SPMs and those with MPMs. The correlation between MC1R variants and melanoma risk has been widely described in different populations (Tagliabue et al, 2015 ; Pinto et al, 2016 ; Pellegrini et al, 2019 ). The MC1R gene is considered a master regulator of pigment production and distribution throughout the skin (pigmentary function) (Puig et al, 2005 ) as well as a regulator of antioxidant defenses and DNA repair mechanisms (non-pigmentary function) (Rees, 2004 ; Abdel-Malek et al, 2014 ), thereby supporting its role in melanoma development.…”

Skin pigmentation and its control: From ultraviolet radiation to stem cells

“…Significant variation exists amongst MC1R and the resultant phenotypes. In the paediatric population, those with cutaneous melanoma have higher rates of MC1R variants than adult populations with cutaneous melanoma, with V60L and D294H having the most influential association 53 . Wendt et al documented that in Austria, MC1R variants are an independent risk factor for melanoma in females but not males 54 .…”