Total Nevus Count Research Articles

A Major Quantitative-Trait Locus for Mole Density Is Linked to the Familial Melanoma Gene CDKN2A: A Maximum-Likelihood Combined Linkage and Association Analysis in Twins and Their Sibs

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.

Natural history of dysplastic nevi

Dysplastic nevi are markers of melanoma risk and potential precursors of melanoma. Few studies have addressed the natural history of dysplastic nevi. Our purpose was to describe the changes observed in nevi over time in a cohort of our patients with dysplastic nevi. We used a historical cohort design to study 153 patients with dysplastic nevi observed for a minimum of 5 years. Physical examination at completion of the study was compared with baseline overview and close-up photographs. Lesions excised during the study interval were assessed for history of change. Fifty one percent of all evaluated nevi (297 of 593) showed clinical signs of change during an average follow-up of 89 months. New nevi were common in adulthood and continued to form in more than 20% of patients older than 50 years of age. Nevi were observed to become more clinically atypical, less clinically atypical, and disappear in all age groups. In this small cohort rates of nevus change were not correlated with personal or family history of melanoma, sex, or total number of nevi. Total nevus counts and rates of nevus change were correlated with age. Dysplastic nevi remain clinically dynamic in adulthood. Our data suggest that the decrease in counts of dysplastic nevi associated with increasing age is only partly explained by the disappearance of nevi over time and probably reflects a tendency to larger numbers of nevi among more recent birth cohorts.