Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

The octamer motif ATGCAAAT is recognized indistinguishably by two mammalian transcription factors: one that is expressed ubiquitously and referred to here as Oct-l, and another, Oct-2, that is expressed in lymphoid cells. We report the cDNA cloning of the human oct-1 gene, which encodes Oct-l, by screening kgtl 1 recombinant phage in situ for octamer motif-specific DNA binding. Transcriptional regulation depends largely on the sequence-specific interaction of trans-activator proteins with cis-acting promoter elements. Sequence-specific trans-activators contain two essential domains for function: a DNA-binding domain and a trans-activation domain. As first shown by fusion of the bacterial lexA DNA-binding domain to the yeast GAL4 trans-activation domain (Brent and Ptashne 1985), these domains can be interchanged. The specificity of transcriptional activation is conferred by the DNA-binding domain, which targets the trans-activator to the promoter carrying a corresponding DNA-binding site(s) (for review, see Ptashne 1988). To date, trans-activation domains have displayed little promoter specificity. For example, the yeast GAL4 trans-activator can stimulate a variety of promoters in mammalian cells provided that GAL4

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.

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