This study investigated the immunohistochemical expression of retinoblastoma (RB) protein and p16 protein in 10 neuroendocrine carcinomas (NECs), in comparison to two mixed-type NECs; 28 squamous cell carcinomas (SCCs), and 12 carcinosarcomas (CSs) from patients with esophageal cancer.
Low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS, or high expression of (or IHC-positive) CDC25B and p16 are potential biomarkers for predicting the response of esophageal cancer patients treated with chemo(radio)therapy.
Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002).
Epigallocatechin-3-gallate inhibits growth and induces apoptosis in esophageal cancer cells through the demethylation and reactivation of the p16 gene.
The frequencies of non-synonymous single nucleotide variants (SNVs) in the TP53 family members TP63 and TP73 were relatively low, although genes with increased frequencies of SNVs were as follows: PTEN (11.7%) in breast cancer, CDKN2A (11.1 and 9.6%) in pancreas and head and neck cancers, and ATM (18.0 and 11.1%) in liver and esophageal cancers.
The p53 expression was positive in 67.5% of tumor tissue, 20.0% of adjacent non-tumoral tissue and 1.8% of normal esophageal tissue. p16 was positive in 11.6% of esophageal cancer cases and 4.7% of adjacent non-tumoral tissue. p16 was undetectable among control group samples. p53 and p16 levels were not significantly associated with the HPV status.
Betel quid and tobacco chewing habit synergistically with p16 methylation elevated the risk for esophageal cancer development (adjusted odds ratio (OR) = 6.88, 95% confidence interval (CI) = 1.64-28.81, p = 0.003 for betel quid chewing and adjusted OR = 7.02, 95% CI = 1.87-26.38, p = 0.001 for tobacco chewing).
Then demethylation caused by 5-aza-2'-deoxycytidine increased the p14ARF mRNA expression level in esophagus cancer cell lines. p14ARF methylation was found in 48% (24 of 50) of ESCC patients but only in 18% (9 of 50) corresponding noncarcinoma tissues (P = 0.001).
A tissue microarray containing 86 specimens from esophageal cancer and 40 specimens from adjacent non-cancer tissue was constructed to survey the expression of p53, p16 and COX-2 by immunohistochemistry.
Treatment of human esophageal cancer KYSE 510 cells with 5-50 microM of EGCG for 12-144 h caused a concentration- and time-dependent reversal of hypermethylation of p16(INK4a), retinoic acid receptor beta (RARbeta), O(6)-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) genes as determined by the appearance of the unmethylation-specific bands in PCR.
The vast majority of esophageal cancers have inactivation of the p53 and p16 genes at an early stage followed by defects in genes such as APC, Rb and cyclin D1 at later stages of progression.
The dual hits (concomitant loss) of pRb and p16INK4a expression suggest that these two components are not mutually exclusive, and can both be altered in a significant proportion of primary ESCCs serving as putative diagnostic markers for esophageal cancer.
The p16INK4 tumor suppressor gene encodes a protein that inhibits cyclin-dependent kinase 4, and its homologous deletion is common in human breast cancer. p16INK4 gene transfer has been reported to be efficacious in inducing growth inhibition of various human tumors such as brain, lung, prostate, and esophageal cancers.
The relatively low rate of p16 mutation observed here coupled with the high frequency of loss of heterozygosity on chromosome 9 suggests that one or several tumor-suppressor gene(s) distinct from p16 may be the target(s) of allelic deletion in most esophageal cancers or that p16 is inactivated in another way.
These results may have implications regarding the design of clinical trials using p16 gene replacement strategies for intervention in esophageal cancers.
In order to determine whether CDKN2A and CDKN2B are frequent targets of 9p21 deletion in esophageal carcinogenesis, we have now analyzed 60 primary esophageal cancers for mutations in both exons 1 and 2 of CDKN2A and CDKN2B by direct sequencing of PCR amplified genomic DNAs.