Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population

A Sameer,Safiya Abdullah,Zaffar A Shah,Mushtaq A Siddiqi,Nissar A Chowdri

doi:10.1186/1479-7364-5-5-441

A Sameer, Safiya Abdullah + Show 3 more

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https://doi.org/10.1186/1479-7364-5-5-441

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Abstract

The development and progression of colorectal cancer (CRC) is a multi-step process, and the Wnt pathways with its two molecular gladiators adenomatous polyposis coli (APC) and β-catenin plays an important role in transforming a normal tissue into a malignant one. In this study, we aimed to investigate the role of aberrations in the APC and β-catenin genes in the pathogenesis of CRC in the Kashmir valley, and to correlate it with various clinicopathological variables. We examined the paired tumour and normal-tissue specimens of 86 CRC patients for the occurrence of aberrations in the mutation cluster region (MCR) of the APC gene and exon 3 of the β-catenin gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the APC gene was also carried out using methylation-specific PCR (MS-PCR). The overall mutation rate of the MCR of the APC gene among 86 CRC cases was 12.8 per cent (11 of 86). Promoter hypermethylation of APC was observed in 54.65 per cent (47 of 86) of cases. Furthermore, we found a significant association between tumour location, tumour grade and node status and the methylation status of the APC gene (p ≤ 0.05). Although the number of mutations in the APC and β-catenin genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, APC, of the Wnt pathway in the development of CRC in the Kashmiri population.

Highlights

Colorectal cancer (CRC) is a major cause of mortality and morbidity, and the third most common malignancy in the world.[1]
It has been suggested that CRC is a multi-step process which arises from cumulative aberrations of a number of different genes or from epigenetic changes in DNA at different stages of development and progression.[6,7]
All but one case had adenocarcinoma and only one had squamous cell carcinoma (SCC) of Mutation analysis of adenomatous polyposis coli (APC) The overall mutation rate of the mutation cluster region (MCR) of APC among the 86 patients was 12.8 per cent (11 of 86). This is in contrast to other studies that have reported APC as the main gene to undergo aberration in CRC, with a frequency of about 60 per cent

Summary

Introduction

Colorectal cancer (CRC) is a major cause of mortality and morbidity, and the third most common malignancy in the world.[1] The incidence of this malignancy shows considerable variation among racially or ethnically defined populations in multiracial/ethnic countries. It is the fourth most common cancer in men and the third most common in women worldwide.[1] Kashmir has been reported as being a high-incidence area for gastrointestinal (GIT) cancers.[2,3] In the Kashmir valley, CRC represents the third most common GIT cancer after oesophageal and gastric cancer.[4,5].

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