The p16 coding gene is often mutated in glioblastomas, pancreatic adenocarcinomas and melanoma-prone pedigrees, but, until recently, the significance of these allelic variants has remained unclear.
The significance of p16 mutations in gastric tumorigenesis was examined by assessing p16 mutations as well as loss of heterozygosity (LOH) on 9p in 13 gastric adenomas and 45 adenocarcinomas.
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.
Using PCR-SSCP, we analyzed exons one (126 bp) and two (307 bp) of the MTS1 gene to determine the incidence of mutation in a population of 50 primary breast adenocarcinomas and corresponding normal tissue.
These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic 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.
We determined the prevalence of allelic loss at 9p21 and mutations in CDKN2 in esophageal adenocarcinomas and investigated the order in which they occurred relative to the development of aneuploidy and cancer during neoplastic progression.
In search of genetic constellations that might indicate the progression of some PILs toward an invasive phenotype, mutations at both the K-ras and p16 genes were sought within PILs of 10 pancreata resected for adenocarcinoma.
Our data suggest that promoter hypermethylation with LOH is a common mechanism for inactivation of p16 in the pathogenesis of esophageal adenocarcinomas.
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.
In the rat, 94% of adenocarcinomas induced by the tobacco specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone were hypermethylated at the p16 gene promoter; most important, this methylation change was frequently detected in precursor lesions to the tumors: adenomas, and hyperplastic lesions.
MTS1 gene mutations were detected in 2 adenocarcinomas only; gene methylation was observed in 17 of 72 cases (24%) without any correlations with the variables investigated.
In contrast, p16 expression was weak in normal endometrium and increased in most cases of hyperplasia, but negative or minimally positive in 74% of the carcinomas and the Hec1B adenocarcinoma cell line, and there was no significant association with Rb immunostaining.
The purpose of the present study was to evaluate patterns of p16 expression in a well-characterized cohort of prostatic adenocarcinomas while exploring potential associations between alterations of p16 and clinicopathological variables.
Abnormalities involving the p16 (also known as cyclin-dependent kinase N2 [CDKN2], p16 [INK4a], or MTS1) and p53 (also known as TP53) tumor suppressor genes are highly prevalent in esophageal adenocarcinomas.
Both the adenocarcinoma and squamous cell carcinoma components revealed an inverse correlation between the expression pattern of p16 and RB proteins (p < 0.05).
The pancreatic carcinomas with homozygous p16 deletions were largely devoid of nuclear staining (admixed nonneoplastic cells served as internal positive controls); only one adenocarcinoma each reacted with DCS-50 and the polyclonal antibody, and five were positive with ZJ11, suggesting that nonspecific nuclear staining can occur under certain conditions.
Methylation of the p14ARF gene occurred more frequently in well-differentiated adenocarcinomas (p = 0.005), whereas the p16INK4a gene was more often methylated in poorly differentiated adenocarcinomas (p = 0.002).
The molecular changes in small cell carcinomas were similar to those of adenocarcinomas occurring at this site, with a high frequency of p53 (75%) and p16INK4a (33%) abnormalities, and a low frequency of deleted in pancreatic carcinoma-4 inactivation (0%) and K-ras codon 12 mutations (17%).