Novel polymorphism in p21(waf1/cip1) cyclin dependent kinase inhibitor gene: association with human esophageal cancer

p21(waf1/cip1), an important regulator of the cell cycle, binds to PCNA and acts as a mediator of the growth suppressing and apoptosis promoting funct ions of p53. We report a hitherto unobserved polymorphism in the carboxy te rminal domain (codon 149) of p21(waf1/cip1) gene, the domain encoding the P CNA binding motif, The codon 149 polymorphism (G (A) under bar T-->G (G) un der bar T) was observed in 42 of 50 (84%) esophageal squamous cell carcinom as (ESCCs) and eight of 50 (16%) normal individuals, The resultant amino ac id substitution from aspartate to glycine may have vital implication in PCN A mediated cell cycle regulation by p21(waf1/cip1). The second polymorphism at codon 31, involving a C-->A transversion at nucleotide 168 (AG (C) unde r bar-->AG (A) under bar) changing the amino acid from serine to arginine, was observed in 2/50 (4%) ESCCs at a relatively lower frequency in the Indi an population than that reported in the West. No significant association wa s observed between p21(waf1/cip1) polymorphism at codon 149 and p21(waf1/ci p1) protein expression in ESCC in this cohort of patients. Interestingly, t he frequency of p21(waf1/cip1) variants (codon 149) in ESCCs (18 of 19 case s) with wild-type p53 was significantly higher than in tumors with p53 muta tions, suggesting that this polymorphism affects the p53 pathway and may pl ay an important role in esophageal tumorigenesis, Analysis of p21(waf1/cip1 ) expression in relation to p53 gene and protein status revealed its induct ion by p53-dependent as well as independent pathways in esophageal tumorige nesis.