Association between polymorphism in p21(Waf1/Cip1) cyclin-dependent kinaseinhibitor gene and human oral cancer

The cyclin-dependent kinase inhibitor genep21(Waf1/CiP1) plays a central ro le in inducing cellular growth arrest, terminal differentiation, and apopto sis, Alterations in this gene may adversely affect regulation of these proc esses and increase susceptibility for canter. We have recently reported a n ovel polymorphism in the p21(Waf1/Cip1) gene in the Indian population and i ts association with esophageal cancer. An A-->G transition at codon 149 res ulted in amino acid substitution from aspartate to glycine in the prolifera ting cell nuclear antigen binding COOH-terminal domain of p21(Waf1/Cip1) th at may affect PCNA-p21(Waf1/Cip1) interactions, thereby affecting regulatio n of cellular proliferation, and may increase susceptibility for developmen t of cancer. In a parallel study in our laboratory, we searched for putativ e p21(Waf1/Cip1) mutations in oral premalignant and malignant lesions, No s omatic mutation was detected in exon 2 of p21(Waf1/Cip1). Interestingly, a codon 149 polgmorphism variant (A-->G) was identified in 11 of 30 (37%) pre malignant lesions (7 of 19 hyperplastic lesions and 4 of 11 dysplastic lesi ons) and 11 of 30 (37%) squamous cell carcinomas (SCCs), This codon 149 var iant was also identified in paired lymphocytes of all of the patients with premalignant lesions and SCCs harboring the variant allele, suggesting the occurrence of a polymorphism, Lymphocyte DNA isolated from 50 unrelated age - and gender-matched healthy subjects was screened for this polymorphism. S even of 50 (14%) normal controls harbored the A-->G codon 149 variant allel e, Immunohistochemical analysis of p21(Waf1/Cip1) protein expression showed immunoreactivity in 19 of these 30 (63%) oral premalignant lesions and 16 of 30 (53%) SCCs, The most intriguing features of the study were: (a) the s ignificant increase in frequency of this polymorphism not only in patients with oral SCCs (P = 0.038), but also in patients with premalignant lesions (P = 0.038), compared with normal controls; and (b) the significantly highe r frequency of p21(Waf1/Cip1) variants (codon 149) in oral premalignant les ions (10 of 11 cases) and SCCs (11 of 11 cases) with wildtype p53 (P = 0.04 5) than In lesions with p53 mutations, suggesting that this polymorphism af fects the p53 pathway and may play a vital role in oral tumorigenesis. Furt hermore, overexpression of p21 protein in oral lesions harboring missense m utations in the p53 gene suggest a p53-independent role for p21 in the path ogenesis of oral cancer.