Inheritance of Nevus Number and Size in Melanoma and Dysplastic Nevus Syndrome Kindreds

Abstract

Previous studies of the genetics of melanoma have focused on the dysplastic nevus syndrome (DNS). The variability in clinical and histopathological expression of affected individuals, however, has made definition and diagnosis of the syndrome difficult and subjective. Independent of the DNS, case-control studies have demonstrated the total number of nevi to be a significant risk factor for melanoma. In this article, we report results of genetic analyses of two quantitative nevus phenotypes that can be measured objectively in all subjects: the total number of nevi on an individual (TNN) and total nevus density (TND), a derived phenotype which incorporates both number and size of nevi. Ten kindreds ascertained for multiple cases of DNS-melanoma (multiplex ascertainment) and 16 kindreds and 19 solitary cases ascertained from a sequential list of melanoma cases without regard for family history (simplex ascertainment) were studied. Both phenotypes exhibited increased levels in relatives of probands compared with those in spouse controls. While neither TNN nor TND exhibited evidence for a major factor in the simplex pedigrees, a major factor was strongly indicated in the multiplex kindreds for TND. When both phenotypes were examined in more detail in the multiplex kindreds, the phenotype incorporating nevus size, TND, fit a mendelian pattern of inheritance better than the TNN. Significant residual familial correlations were found for both phenotypes. 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 the multiplex kindreds.

The Genetic Evolution of Melanoma from Precursor Lesions

“…32 The clinical phenotype of multiple dysplastic nevi has been shown to be a reliable predictor of melanoma risk. 33,34 However, the relevance of the histopathological features that are attributed to dysplastic nevi has remained controversial, and there is considerable variation in the way in which dysplastic nevi are diagnosed and managed clinically. 15 We therefore avoided the term "dysplastic" in grading individual areas and instead asked the participating pathologists to assign each lesion a probability of malignancy.…”

Longitudinal Assessment of the Nevus Phenotype in a Melanoma Kindred

“…Lesions o2 mm in diameter were excluded to reduce the possibility of erroneously including freckles in the TNN (Nicholls, 1973). TND was estimated by calculating the area of all nevi using the formula Spr 2 divided by the estimated body surface area of the individual, as described previously (Goldgar et al, 1991;Meyer et al, 1992).…”

The Molecular Pathology of Melanoma: An Integrated Taxonomy of Melanocytic Neoplasia

“…For this assessment clinical examination is sufficient, and histological examination does not provide additional information. It is also firmly established that nevus size is a heritable trait (68). The higher the count of large nevi, the higher the melanoma risk (69).…”