High naevus count and MC1R red hair alleles contribute synergistically to increased melanoma risk

A high total body naevus count is the highest risk factor for melanoma; the red hair colour phenotype of red hair, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma. To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk. The Brisbane Naevus Morphology Study drew 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, Brisbane Longitudinal Twin Study and QSkin study. We examined pigmentation characteristics, total body naevus ≥5mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in the very high incident UV setting of Queensland, Australia. Cases were older than controls (median 57 vs 33 years). Compared to individuals with dark brown hair and 0-4 naevi, individuals with red hair and 20+ naevi had a melanoma OR 10·0 (95%CI 4·2-24·3). Individuals with MC1R R/R genotype and 20+ naevi ≥5mm had a melanoma OR 25·1 (95%CI 8·4-82·7) compared to WT/WT individuals with 0-4 naevi. The highest risk group, Australian men with MC1R R/R genotype and 20+ moles, had an absolute risk of melanoma to age 75 of 23·3%, compared to 0·8% for men with WT/WT genotype and 0-4 naevi. Patients living in a high incident UV setting with many large naevi and the red hair colour phenotype, particularly those with MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers and should undergo intensive physician-led surveillance.