Aberrant promoter methylation and reduced expression of p16 gene in esophageal squamous cell carcinoma from Kashmir valley: a high-risk area

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancer in Jammu and Kashmir region of India and has multi-factorial etiology involving dietary habits, genetic factors, and gene environmental interactions. Inactivation of the p16 gene expression by aberrant promoter methylation plays an important role in the progression of esophageal carcinoma. In the present investigation, we have studied the role of p16 promoter methylation in 69 histopathologically confirmed ESCC tissues and compared it with corresponding normal adjacent tissues for DNA methylation in the CpG island in the p16 promoter region by methylation-specific polymerase chain reaction (MSP) and p16 protein expression by immunoblotting. The results showed loss of p16 expression in 67% (46/69) of tumor tissues compared to only 3% in control tissues (2/69). Promoter methylation was observed in 52% (36/69) of tumor tissues and it gradually increased with the increasing severity of histological grades of the cancer (P = 0.0001). Loss of p16 expression with promoter methylation was observed in 26 of 36 cases (72%). Analysis of patients dietary habits revealed a strong association between promoter methylation and high consumption of hot salted tea (P < 0.05) which is a most favourite drink commonly consumed by Kashmiri people.

Ki-67 and ProExC are useful immunohistochemical markers in esophageal squamous intraepithelial neoplasia

“…P16 is a cyclin-dependent kinase inhibitor that downregulates progression through the G1-S transition checkpoint of the cell cycle. Inactivation of p16 plays a critical role in ESCC carcinogenesis [29]. Mechanisms of inactivation of p16 proteins include somatic mutation of the encoding gene CDKN2, homozygous deletion of the gene, or hypermethylation of the gene.…”

Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population

“…The Kashmir Valley is located in the northern part of India, walled by the mighty Himalayas, its unique ethnic population live in discrete temperate environmental conditions and have distinctive eating habits, which play an overwhelming role in the development of GIT cancers over the genetic factors (Murtaza et al, 2006;Salam et al, 2009;Sameer et al, 2010a,b). As previously reported (Siddiqi et al, 1992), the etiology and incidence of various GIT cancers in this population have been attributed to the probable exposure to nitroso compounds, amines and nitrates reported to be present in the local foodstuffs.…”

Identification of GPX3 Epigenetically Silenced by CpG Methylation in Human Esophageal Squamous Cell Carcinoma

“…Epigenetic changes such as promoter DNA methylation can induce inactivation of tumor suppressor genes that are important to prevent carcinogenesis. Recently, a number of genes, e.g., ECRG4 [4], p16 [5], HPP1 [6], DLC1 [7], UCHL1 [8], and TSPYL5 and PPP1R14A [9], have been found to be aberrantly methylated in ESCC. Nevertheless, novel and specific methylation-sensitive tumor suppressor genes in ESCC remain to be identified.…”