Genotypephenotype Correlations

The International Melanoma Genetics Consortium has estimated the penetrance of melanoma in CDKN2A mutation-positive family members between different geographical locations to range from 58% to 91% by the age of 80 years, with an average of 67%.[22] The broad confidence intervals make it impossible to provide precise melanoma risks. Mutations affecting only p16 compared to those affecting both p16 and p14ARF showed a trend (although not statistically significant) toward a higher penetrance in the latter.

Mutations affecting only p14ARF have been described in two melanoma families and an individual with multiple melanomas. Additionally, another multiple melanoma case and two other families have deletions of part of chromosome 9p that encompass both p16 and p14ARF coding sequences. Each of the latter and one of the p14ARF-only mutated families have cases of nervous system tumors.[7] These observations suggest that whereas both p16 and p14ARF predispose to melanoma, it is mutation of p14ARF that predisposes to nervous system tumors.

In families with an increased incidence of pancreatic cancer there is no clear correlation with the position or type of mutation in CDKN2A . Similarly, there is no obvious correlation between position (or type) of mutation within the gene and the development of neviā€”this is particularly well highlighted by families with the same mutation being either extremely moley, or conversely, relatively free of nevi. One especially important obser vation is that abundance of nevi is not a predictor of CDKN2A mutation status. High numbers of nevi are also seen in nonmutation carriers within mutation-positive families (illustrated in the pedigree shown in Fig. 3).

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