Distinct Involvement of 9p21-24 and 13q14.1-14.3 Chromosomal Regions in Raw Betel-Nut Induced Esophageal Cancers in the State of Meghalaya, India

Abstract

<b>Background:</b> Raw betel nut (RBN) chewing is an important contributing factor for esophageal squamous cellcarcinoma (ESCC), although associated genomic changes remain unclear. One difficulty in assessing the effectsof exclusively RBN induced genetic alterations has been that earlier studies were performed with samples ofpatients commonly using tobacco and alcohol, in addition to betel-quid. Both CDKN2A (at 9p21) and Rb1 gene(at 13q14.2) are regarded as tumor suppressors involved in the development of ESCC. Therefore, the presentstudy aimed to verify the RBN’s ability to induce ESCC and assess the involvement of CDKN2A and Rb1 genes.<br/><b>Methods</b>: A panel of dinucelotide polymorphic markers were chosen for loss of heterozygosity studies in 93samples of which 34 were collected from patients with only RBN-chewing habit. Promoter hypermethylationwas also investigated. <br/><b>Results</b>: Loss in microsatellite markers D9S1748 and D9S1749, located close to exon 1β ofCDKN2A/ARF gene at 9p21, was noted in 40% ESCC samples with the habit of RBN-chewing alone. Involvementof a novel site in the 9p23 region was also observed. Promoter hypermethylation of CDKN2A gene in the sampleswith the habit of only RBN-chewing alone was significantly higher (p=0.01) than Rb1 gene, also from the sampleshaving the habit of use both RBN and tobacco (p=0.047). <br/><b>Conclusions</b>: The data indicate that the disruption of9p21 where CDKN2A gene resides, is the most frequent critical genetic event in RBN-associated carcinogenesis.The involvement of 9p23 as well as 13q14.2 could be required in later stages in RBN-mediated carcinogenesis.