Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site-specific, but whose effect sizes are predominantly stronger on the lower limbs.
Four SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6 and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model; IRF4 rs12203952 showed the strongest association with log naevus count (relative risk 1·56, P < 0·001).
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.
In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 × 10<sup>-49</sup>) and NID1 (P = 6.4 × 10<sup>-14</sup>), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 × 10<sup>-10</sup>).
Interestingly, we observed an increased risk of melanoma in subjects with darker skin and lower nevus count, usually considered at low risk, when carrying MC1R polymorphisms.
Development of a melanoma risk prediction model incorporating MC1R genotype and indoor tanning exposure: impact of mole phenotype on model performance.
Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants.
Penetrance of CDKN2A gene was found to be significantly influenced by host factors (nevus phenotypes and sunburn) on one hand and by variants of MC1R gene (RHC variants consistently associated with red hair and fair skin) on the other hand.
The relationships between MC1R gene variants and red hair, skin reflectance, degree of freckling and nevus count were investigated in 2331 adolescent twins, their sibs and parents in 645 twin families.
The results suggest that strong p16 expression in the villous mesenchyme may be responsible in part of the morbidity of the moles, and the key of cancer progression in the choriocarcinomas would be a fast cell-cycle turnover.