Genes and Nevogenesis

Abstract

Total nevus count has been shown to be a strong and consistent predictor of melanoma risk in adult population [1]. Twin studies have been a tremendously useful tool to tease out the relative contributions of genetic and behavioral risk factors for disease. Exploring differences between monozygotic and dizygotic twin pairs allows for the assessment of the relative contribution of genetic and environmental factors for a specific trait. Several twin cohorts have been assembled to assess the roles of genetics and UVR in nevus phenotype. In general, total nevus counts have been shown to be highly influenced by genetic factors. Twin studies have estimated that up to 60 % of the variation in nevus counts can be attributed to genetic factor [2–4]. One of the first studies to evaluate nevus phenotype in twins found that in 23 monozygotic (MZ) and 22 dizygotic (DZ) twin pairs, a strong correlation (r = 0.83) for total body nevus counts was found in the monozygotic twins. However, when assessing the dizygotic twins, the correlation disappeared (r = −0.24) [3]. In a parallel study exploring a larger cohort of 221 twin pairs, the intraclass correlation for total nevus count in MZ pairs was 0.94 (95% CI, 0.92–0.96) compared with 0.63 (0.52–0.74) for the DZ pairs [5]. These results were corroborated in a study by Goldgar et al. in a cohort of kindreds selected from dysplastic nevus syndrome and melanoma families. Investigators found that total nevus number (TNN) and total nevus density (TND) were highly correlated within families [6]. Parameter estimates from the best-fitting genetic model indicated that a major gene may be responsible for 55% of the phenotypic variability of TND in kindreds. Further investigations utilizing genome-wide association studies suggest that variants on 9p and 22q harbor genes associated with increased nevus counts [7]. In addition, the exploration of other genes associated with pigmentation, such as the melanocortin-1 receptor (MC1R) and OCA2, may provide additional insights for nevus development. To date, a “nevus gene” has not been identified, but as with many other characteristics, nevi are most likely polygenic, with many individual genes working in concert to determine an individual’s overall nevus phenotype.