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The cyclin kinase inhibitor WAF1/CIP1, also termed CDKN1, mediates p53-induced cell cycle arrest in response to DNA damage. This property makes it an attractive tumour-suppressor candidate for a p53-associated tumour-suppressor gene. In order to investigate the role of WAF1/CIP1 in the pathogenesis of primary human brain tumours we performed single-stranded conformation polymorphism (SSCP) analysis and direct sequencing of exon 2 of the gene in a representative series of 158 brain tumours and corresponding blood samples. In addition, all tumours were examined for mutations in exons 5-8 of the p53 gene. Analysis of WAF1/CIP1 revealed multiple polymorphisms, the most abundant being AGC--&gt;AGA (Ser--&gt;Arg) at codon 31 with an allele frequency of 8.5%. Less common polymorphisms included GTG--&gt;GGG (Val--&gt;Gly) at codon 25, GCC--&gt;ACC (Ala--&gt;Thr) at codon 64, CGC--&gt;CTC (Arg--&gt;Leu) at codon 32, GGC--&gt;AGC (Gly--&gt;Ser) at codon 14 and GCG--&gt;GTG (Ala--&gt;Val) at codon 39 each with an allele frequency of 0.3%. These polymorphisms were all located in a conserved region of exon 2. Two of the polymorphisms were also seen in a group of 157 healthy controls indicating that WAF1/CIP1 polymorphisms do not predispose to cancer. None of the tumours included in our series showed a somatic mutation in WAF1/CIP1. All samples were also analysed for loss of heterozygosity on the short arm of chromosome 6 in the region of the WAF1/CIP1 locus. Allelic loss was observed in only one patient with a glioblastoma. Mutations in the p53 gene were found in 22 of 158 tumours. No association was found between any polymorphism of the WAF1/CIP1 gene, p53 mutations and histopathological tumour type. Our data indicate that WAF1/CIP1 mutations are probably not involved in the formation of primary human brain tumours.

Multiple polymorphisms, but no mutations, in the WAF1/CIP1 gene in human brain tumours