MTS-1 is a candidate tumor suppressor gene on chromosome 9p21-22, a region frequently observed to have loss of heterozygosity in esophagus squamous cell carcinomas and pancreatic ductal adenocarcinomas.
Mutational analysis of the p16/CDKN2 gene was conducted by direct sequencing of the whole coding sequence (exons 1-3 and flanking splicing sites) in 21 esophageal squamous-cell carcinomas and 3 adenocarcinomas from a high-incidence area of Italy.
Homozygous deletion of p16 appears to be common in esophageal squamous cell carcinomas but in adenocarcinomas, both gene deletion and transcriptional silencing of p16 were infrequent.
Recent studies have reported frequent p16 gene deletions in cell lines from squamous cell carcinomas of the head and neck (SCCHN), although the prevalence of alterations was variable in primary tumors.
These findings indicate that p16MTS1/CDK4I is frequently inactivated by gene mutation, hypermethylation, and allelic deletions in a significant subset of squamous cell carcinomas of larynx.
The loss of p16 expression and overexpression of cyclin D1 may be useful prognostic indicators in patients with squamous cell carcinomas of the esophagus.
The combination of the lack of p16INK4 and/or Rb expression increased from benign lesions (14.3%), through VIN I (60%) and VIN III (60%), to invasive squamous cell carcinoma (72%), thus supporting the postulation that alterations in p16INK4 or Rb could be significant events in progression of disease.
Hence, it was possible to restore a functional pRB pathway in an oral squamous cell carcinoma line by inducing re-expression of endogenous p16ink4a in response to treatment with a demethylating agent.
Three cases of TCC with SCC had p16/p19 deletion, hypermethylation of the p16 promoter, or LOH on 9p21 only in the SCC components, suggesting that these molecular alterations occurred preferentially in SCC.
The timing for p16 methylation was recapitulated in human SCCs where the p16 gene was coordinately methylated in 75% of carcinoma in situ lesions adjacent to SCCs harboring this change.
p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use.
Our results indicate that (1) loss of the p16 protein may constitute an early event in the development of these HNSC, (2) the reciprocal expression of p16 and Rb suggests a tight regulatory interaction between these genes in HNSC tumorigenesis, and (3) alteration in at least one of these genes might be required for HNSC development and progression.