Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon

Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and...

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Published in:	Journal of cancer research and therapeutics Vol. 20; no. 1; pp. 268 - 274
Main Authors:	Sarangi, Jayati, Das, Prasenjit, Ahmad, Aijaz, Sulaiman, Mohamed, Ghosh, Shouriyo, Gupta, Brijnandan, Panwar, Rajesh, Pal, Sujoy, Yadav, Rajni, Ahuja, Vineet, Sen, Sudip, Upadhyay, Asish D, Dash, Nihar R, Sharma, Atul, Gupta, Siddhartha D
Format:	Journal Article
Language:	English
Published:	India Medknow Publications & Media Pvt. Ltd 01-01-2024
Subjects:	Aberrant Crypt Foci - diagnosis Aberrant Crypt Foci - genetics Aberrant Crypt Foci - pathology Colon Colon - pathology Colonic Neoplasms - pathology Colorectal cancer Colorectal Neoplasms - pathology Genes Genes, Tumor Suppressor Humans Hyperplasia - pathology Intestinal Mucosa - pathology Methylation Precancerous Conditions - pathology
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Summary:	Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear β-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0973-1482 1998-4138
DOI:	10.4103/jcrt.jcrt_1573_22