MC1R: three novel variants identified in a malignant melanoma association study in the Spanish population

The human melanocortin-1 receptor (MC1R) gene, which plays a crucial role in pigmentation, also appears to be important in malignant melanoma (MM). This case–control study in the Spanish population included 116 consecutive MM patients and 188 controls frequency matched for sex and age. Sequence analysis of the entire coding region of MC1R was performed, identifying 21 variants, all of them previously reported except for three novel non-synonymous changes: Ser41Phe, Met128Thr and Asn281Ser. Simulated structural analyses suggested disruption of the local structure around Phenylalanine 41, possible destabilization of the hydrophobic interior of the molecule in Threonine 128 and that Asparagine 281 could be in a region of functional importance. The fact that these three novel variants were not present in 1,000 healthy individuals tested adds further weight to them having putative adverse effects on the functional protein. Six variants, all non-synonymous changes, were individually associated with MM risk (Arg160Trp, Asp294His, Val60Leu, Val92Met, Ile155Thr and Arg163Gln). Carrying two non-synonymous variants was associated with much higher risk of MM (odds ratio: 10.44, 95% confidence interval = 4.48–24.33, P = 5 × 10−8) and haplotype analysis, verified by cloning, confirmed that this is predominantly due to carrying each on a different chromosome. Our results suggest that both red hair colour (RHC) and non-red hair colour variants, and possibly other rare non-synonymous variants, in MC1R are implicated in the development of MM. In addition to carrying MC1R variant alleles, having blond/red hair and childhood sunburns were independent risk factors for MM.