Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study.

Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene-environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10-18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p = 0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p < 0.0001), and nevus densities were higher on sun-exposed sites (92 per m2) than sun-protected sites (58 per m2) (p < 0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95%CI 0.92-0.96) than in DZ pairs (0.61, 95%CI 0.49-0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi.

Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations.

Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0-11. 1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1. 6-12.4), nevi on the feet (odds ratio 4.2; confidence interval 1. 4-12.5), total nevus number being at least 100 (nevi > or = 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0-11.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1. 1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1-3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma.