CDKN2 Mutations Research Articles

Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer.

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.

Low frequency of CDKN2 mutation in endometrial carcinomas.

The CDKN2 gene on chromosome 9p21 encodes the p16 inhibitor of cyclin D/cyclin-dependent kinase 4 complexes. Mutations and deletions of CDKN2 have been frequently identified in cell lines, whereas most primary tumors have demonstrated a lower frequency of alteration. To assess the role of CDKN2 in endometrial tumorigenesis, 34 tumor samples were examined for loss of heterozygosity at 9p21 and mutation in CDKN2. To identify tumors that had lost 9p21, samples were genotyped with markers flanking the CDKN2 locus. The frequency of CDKN2 mutation in endometrial carcinomas was determined by single-strand conformation variant analysis and direct sequencing of variants. Of the 34 tumors examined, three revealed loss of 9p21 sequences. Two samples were characterized by point mutations in CDKN2, one of which also showed loss of 9p21 sequences.

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

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.