Aim: This study is directed towards understanding the complex interplay between Human papilloma Virus (HPV) infection and p53 gene alteration in a set of 92 head and neck squamous cell carcinoma (HNSCC) and 28 leukoplakia samples from eastern India.
Methods: DNA isolated from the patient samples were subjected to HPV detection, Loss of Heterozygosity (LOH) analysis of the chromosome 17p region harboring p53, genotyping at the p53 codon 72 locus followed by sequencing of the entire p53 gene to identify somatic mutations. Codon 72 heterozygotes carrying p53 mutation were further cloned and resequenced to identify the allele harboring the mutation.
Results: HPV positivity in the HNSCC samples was found to be 69% while 21% percent of the HNSCC were found to harbor p53 mutations in the coding region of the gene. The absence of p53 mutation in HPV positive tumors was found to be statistically significant compared to the HPV negative tumors (p=0.01) but the same did not hold true for p53 LOH (p=1.0). Among the germline p53 codon 72 heterozygotes, the Pro allele was preferentially lost (p=0.02) while the Arg allele was mutated in majority cases. We also observed that the risk of HPV mediated tumorigenesis increased with the increase in number of Arg alleles at the codon 72 locus.
Conclusion: We propose that genetic and epigenetic alteration of p53 follow distinct pathways during the development of HNSCC from normal epithelium via dysplasia. p53 mutation and HPV mediated p53 inactivation possibly constitute two independent pathways of tumorigenesis.
- p53 LOH
- p53 mutation
- p53 polymorphism
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