DNA was extracted from salivary samples, and next-generation sequencing (NGS) was conducted using a panel covering all 8 known XP genes (classical XP (XP-A to XP-G) and XP variant) and a skin cancer modifier gene, the melanocortin 1 receptor gene (MC1R).
In a case-control study nested within the Nurses' Health Study, we utilized hierarchical modeling approaches, incorporating quantitative information from these functional studies, to examine the association between particular MC1R alleles and the risk of skin cancers.
Study participants were randomized to either a usual-care condition (National Cancer Institute skin cancer pamphlet for diverse skin types) or an MC1R test offer.
Melanocortin 1 receptor (MC1R) has been known to be implicated in different UV-induced damages such as pigmentation, adaptive tanning, and skin cancer.
Even after taking into account potential confounding effects of MC1R genotype and various lifestyle factors that close relatives may share, family history of skin cancer remained strongly associated with early-onset BCC.
We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics.
Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases.
Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk.
Our early-onset BCC risk prediction model incorporating MC1R and indoor tanning extends the work of other skin cancer risk prediction models, emphasizes the value of both genotype and indoor tanning in skin cancer risk prediction in young people, and should be validated with an independent cohort.
Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma).
We also review the current knowledge about the function of MC1R as a skin cancer, particularly melanoma, susceptibility gene and how it modulates the response of melanocytes to UVR.
BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer.
Thus MC1R functional coupling to the cAMP and ERK pathways may involve different structural requirements giving raise to biased effects of skin cancer-associated mutations.
Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 × 10(-4) for melanoma, 7.0 × 10(-7) for SCC, and 0.04 for BCC).
Recent GWAS have identified new candidate determinants of pigmentation traits, but MC1R remains the best characterized genetic determinant of human skin and hair pigmentation as well as the more firmly validated low-penetrance skin cancer susceptibility gene.
However, human MC1R variants associated with red hair, fair skin [red hair color (RHC) phenotype], and increased skin cancer risk display reduced cAMP signaling but activate ERKs as efficiently as wild type in heterologous cells, suggesting independent signaling to ERKs and cAMP in human melanocytes.
The variants within the key pigmentation gene, melanocortin-receptor 1 (MC1R), in particular have been ubiquitously linked with high risk traits and skin cancers involving both pigmentary and non-pigmentary functions and likely interaction with variants in other genes.
The main challenge is to develop specific MC1R agonists that will target melanocytes for skin cancer prevention, or for localization and treatment of metastatic melanoma.
Therefore, treatment of contact allergies or skin cancer with alpha-melanocyte-stimulating hormone or other more stable agonists of melanocortin-1 receptor might ameliorate disease or improve antitumoral immune responses.