WAF1 genotype and endometrial cancer susceptibility

The WAF1 protein, which is a downstream mediator of p53, functions as a uni versal inhibitor of cyclin-dependent kinases. The functional link between p 53 and WAF1 suggests the possibility that alteration in WAF1 function const itutes an alternative mechanism to p53 inactivation. However, there are few reports describing somatic mutations of the WAF1 gene in various human mal ignancies. A polymorphism in the WAF1 gene, a C-to-A transversion at codon 31 resulting in the change of a serine (Ser) to an arginine (Arg), is well known. We found this substitution in 42 of 54 endometrial carcinoma patient s. Allele frequency was 0.44/0.56 for the codon 31 polymorphism (Ser/Arg), the difference of allele frequency between patients and normal controls bei ng significant (0.59/0.41 in normal controls). In addition, individuals car rying the codon 31 Arg allele had a tendency to develop histologically high -grade (odds ratio, 6.11) and clinically advanced tumors. We investigated t he association of the Arg allele with the known risk factors of endometrial carcinomas. Statistical analyses of 42 cases and 32 controls carrying the codon 31 Arg allele identified hypertension (odds ratio, 4.33) and family h istory of cancer (odds ratio, 2.81) as positive risk factors. This implies that these two parameters may be associated with a tendency to develop endo metrial carcinomas in individuals carrying the codon 31 Arg allele of the W AF1 gene. (C) 1999 Academic Press.