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 tu mor. Those family members who also have the atypical mole syndrome are comm only targeted for screening in the belief that they are more likely to be m utant gene carriers. We have correlated the atypical mole syndrome phenotyp e and gene carrier status in five families with germline CDKN2A mutations a nd shown that family members with the atypical mole syndrome were three tim es 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 characteristi cs which best predicted mutant gene carrier status were: nevi on the buttoc ks (odds ratio 4.4; confidence interval 1.6-12.4), nevi on the feet (odds r atio 4.2; confidence interval 1.4-12.5), total nevus number being at least 100 (nevi greater than or equal to 2 mm in diameter) (odds ratio 3.4; confi dence interval 1.0-11.1) and two or more clinically atypical nevi (odds rat io 3.1; confidence interval 1.1-9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick ski n types 1-3. The overlap between gene carriers and nongene carriers was, ho wever, marked: the atypical mole syndrome did not clearly differentiate mut ant gene carriers from those with a normal gene. This study is of significa nce to clinicians as the clinical practice of using the atypical mole syndr ome to identify particular family members for surveillance is shown to be i nappropriate. Until formal gene testing is available, all members of famili es with an excessive number of melanoma cases should be treated as potentia l mutation carriers at increased risk of melanoma.