Association between polymorphism in p21[WAF1/CIP1] cyclin -dependent kinase inhibitor gene and human oral cancer

ABSTRACT

The cyclin-dependent kinase inhibitor gene p21[Waf/Cip1] plays a central role in inducing cellular growth arrest, terminal differentiation and apoptosis. Alterations in this gene may adversely affect regulation of these processes and increase susceptibility for cancer. A novel polymorphism in the p21[Waf/Cip1] gene in the Egyptian population and its association with esophageal cancer had been recently reported. An A->G transition at codon 149 resulted in amino acid substitution from aspartate to glycine in the proliferating cell nuclear antigen binding COOH-terminal domain of p21[Waf/Cip1] that may affect PCNA- p21[Waf/Cip1] interactions, thereby affecting regulation of cellular proliferation and may increase susceptibility for development of cancer. In a parallel study in our laboratory, we searched for putative p21[Waf/Cip1] mutations in oral premalignant and malignant lesions. No somatic mutation was detected in exon 2 of p21[Waf/Cip1]. Interestingly. a codon 149 polymorphism variant [A->G] was identified in 11 of 30 [37%] premalignant lesions [7 of 19 hyperplastic lesions and 4 of 11 dysplastic lesions] and 11 of 30 [37%] squamous cell carcinomas [SCCs]. This codon 149 variant 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. Seven of 50 [14%] normal controls harbored the A->G codon 149 variant allele. Immunohistochemical analysis of p21[Waf/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 significant 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 higher frequency of p21[Waf/Cip1] variants [codon 149] in oral premalignant lesions [10 of 11 cases] and SCCs [11 of 11 cases] with wild-type p53 [p = 0.045] than in lesions with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play a vital role in oral tumorigenesis. Furthermore, overexpression of p21 protein in oral lesions harboring missense mutations in the p53 gene suggest a p53-independent role for p21 in the pathogenesis of oral cancer