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. Moreover, germline mutations identified in some melanoma-prone kindreds last year suggested that CDKN2 is identical to the 9p21-linked melanoma susceptibility gene (MLM); 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.

The INK4 family of cell cycle inhibitors in cancer

“…INK4a RNAs were detected with an exon1a-speci®c probe and ARF messages were detected with an exon1b-speci®c probe (see Figure 3) 1997), or INK4a/ARF (Serrano et al, 1996) were deleted, indicate that p19 ARF is a key contributor to tumor suppression. However, some germline mutations a ecting p16 INK4a in melanoma-prone persons (Hussussian et al, 1994;Gruis et al, 1995;Washimi et al, 1995;Fitzgerald et al, 1996), exclusively target exon 2 of the INK4a gene, apparently without a ecting p19 ARF function . These mutations prevent p16 INK4a from binding CDK4 (Ranade et al, 1995;Koh et al, 1995;Yang et al, 1995;Arap et al, 1997).…”

Genetic testing in familial melanoma: uptake and implications

“…A mutation in CDKN2A-r225-243 del-is frequently found in Dutch melanoma families and is usually referred to as p16-Leiden [7]. Since 1980, these p16-Leiden families have been part of ongoing research and skin screening programs at the Leiden University Medical Center (LUMC) [8].…”

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

“…p16 is itself a tumour suppressor; germline mutations at its locus CDKN2A are principally associated with familial melanoma in humans, with some increased incidence of pancreatic cancer, suggesting particular importance in melanocytes (Gruis et al, 1995;Bennett, 2003;Hayward, 2003;Kefford et al, 2004;Gray-Schopfer and Bennett, 2006). In sporadic cancers, p16 alterations and deletions are more broadly distributed, being found in many types of cancer.…”

“…Humans carrying p16 mutations have not only increased susceptibility to melanoma, but usually also numerous melanocytic naevi (moles), often large (Gruis et al, 1995;Bennett and Medrano, 2002;Bennett, 2003), implying a role for p16 in limiting naevus growth in these families. This led to surmises that moles may be melanocyte clones that have proliferated following a first mutation, then senesced (Bennett and Medrano, 2002;Mooi and Peeper, 2002;Bastian, 2003).…”