We examined known sex-related prognosis factors as they relate to features of melanoma and evaluated the sex-specific role of MC1R in overall and melanoma-specific survival.
Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers.
Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are consequently associated with increased melanoma risk.
Individuals having melanoma in a visibly UV-damaged site were more likely to carry MC1Rrs75570604 (odds ratio [OR] 2.5), 9q31.2 rs10816595 (OR 2.5), and MTAP rs869329 (OR 1.4); these same alleles were more common in MPM patients diagnosed ≤40 years.
Germline variants in the melanocortin-1 receptor (MC1R) gene are common in the population and confer moderate risk for melanoma and basal cell cancers across skin types.
As MC1R has already been suggested to affect melanogenesis and increase risk of developing melanoma, it constitutes one of the best models to understand how natural selection acts on pigmentation.
Radiolabeled α-melanocyte-stimulating hormone (α-MSH) derivatives have a high potential for diagnosis and treatment of melanoma, because of high specificity and binding affinity to the melanocortin-1 receptor (MC1R).
The absolute lifetime risk to age 75 of getting melanoma in Australia is 23.3% for men and 19.3% for women who have 20+ moles and MC1R R/R genotype, compared to just 0.8% for men and 0.7% for women with 0-4 moles and MC1R wildtype/wildtype genotype.
Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma.
<sup>64</sup>Cu- and <sup>68</sup>Ga-labeled alpha-melanocyte-stimulating hormone (α-MSH) analogs targeting the melanocortin-1 receptor are promising positron emission tomography (PET) tracers for detecting melanoma, and the use of <sup>18</sup>F-labeling will further contribute to the detectability and availability.
Although a 3-arm DOTA construct, which has three carboxylic acids, h has been applied for conjugation to many peptides, we investigated if a 4-arm DOTA construct conjugated to peptides improves chemical properties for melanoma imaging of the melanocortin 1 receptor compared to 3-arm DOTA-conjugated peptides.
Most (43/46, 93%) patients had variants in MC1R and 11/46 (24%) had CDKN2A pathogenic variants, but only male sex and having two variants in MC1R correlated with increasing number of melanomas.
In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2, and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes.
The favorable melanoma targeting and imaging properties highlighted the potential of <sup>203</sup>Pb-DOTA-GGNle-CycMSH<sub>hex</sub> as a MC1R-targeting melanoma imaging probe and warranted the evaluation of <sup>212</sup>Pb-DOTA-GGNle-CycMSH<sub>hex</sub> for melanoma therapy in future studies.
Considering that melanocortin 1 receptor is crucial for melanocyte proliferation, regulation and differentiation do the naevi of these darker-skinned individuals have specific features that help identify them as carrying one of these melanocortin 1 receptor variants and do melanomas that develop in dark-skinned melanocortin 1 receptor variant carriers have particular characteristics?
αMSH peptide sequences, evaluated for conjugation to the PEG-Cy5-C' dot nanoparticles, bound to MC1-R with high affinity and targeted melanoma in syngenetic and xenografted melanoma mouse models.
Estimates of second-level parameters gave information about the relative importance of MC1R effects on different pathways, and odds ratio estimates changed depending on prior models (e.g., the change ranged from -21% to 7% for melanoma risk assessment).