Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds

Abstract

The p16 gene (CDKN2) which is localized on chromosome 9p21, is deleted in a significant number of sporadic cancers^1–3. Moreover, germline mutations identified in some melanoma-prone kindreds^4,5 last year suggested that CDKN2 is identical to the 9p21 −linked melanoma susceptibility gene (MLM)⁶; however, failure to identify p16 mutations in all melanoma kindreds putatively linked to 9p21 left some doubts. We have analysed CDKN2 coding sequences in 15 Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome pedigrees, and identified a 19 basepair (bp) germline deletion in 13 of them. All 13 families originate from an endogamous population. The deletion causes a reading frame shift, predicted to result in a severely truncated p16 protein. Interestingly, two family members are homozygous for the deletion, one of whom shows no obvious signs of disease. This surprising finding demonstrates that homozygotes for this CDKN2 mutation are viable, and suggests the presence of a genetic mechanism that can compensate for the functional loss of p16. Our results also greatly strengthen the notion that p16 is indeed MLM.