Inter-relationship between microsatellite instability, thymidylate synthase expression, and p53 status in colorectal cancer: implications for chemoresistance

Sanjay Popat,Richard S Houlston,Richard Wort

doi:10.1186/1471-2407-6-150

Abstract

BackgroundStudies indicate that thymidylate synthase (TS) expression, p53 and mismatch repair status have potential to influence colorectal cancer (CRC) outcome. There is, however, little data on the inter-relationship between these three markers. We sought to investigate whether relationships exist between these markers that might contribute to CRC phenotypes.MethodsFour hundred and forty-one stage I-III CRCs were investigated. p53 status and TS expression were assessed by standard immunohistochemistry methods. Mismatch repair status was determined by assessment of microsatellite instability (MSI) using radiolabelled microsatellite genotyping.Results244 tumours (55%) over-expressed p53, and 259 (58%) expressed high TS levels. 65 tumours (15%) had MSI. A significant relationship between p53 over-expression and high TS expression was observed (p = 0.01). This was independent of MSI status. A highly significant inverse relationship between MSI and p53 status was observed (p = 0.001). No relationship was seen between MSI status and TS expression (p = 0.59).ConclusionRelationships exist between p53 status and TS expression, and MSI and p53 status. These inter-relationships may contribute to the clinical phenotype of CRCs associated with each of the molecular markers. High TS expression is unlikely to account for the clinical behaviour of CRCs with MSI.

Highlights

Studies indicate that thymidylate synthase (TS) expression, p53 and mismatch repair status have potential to influence colorectal cancer (CRC) outcome
Whilst most (~85%) CRCs develop through the chromosomal instability pathway, in which adenoma formation is typified by loss of APC function, and development of invasive malignancy by TP53 mutation [4], a smaller number (~15%) develop as a consequence of mismatch repair (MMR) deficiency
Our results suggest a relationship between TP53 status and TS expression implying that the poor prognosis and chemoresistance observed in studies of CRC patients with either high TS expression or TP53 mutation/p53 over-expression, may have been impacted on by either co-variate

Summary

Introduction

Studies indicate that thymidylate synthase (TS) expression, p53 and mismatch repair status have potential to influence colorectal cancer (CRC) outcome. CRC tumourigenesis is a multi-step phenomenon, typified by a series of genomic events that parallel development of invasive malignancy from normal epithelium through formation of pre-malignant adenomas [4]. Whilst most (~85%) CRCs develop through the chromosomal instability pathway, in which adenoma formation is typified by loss of APC function, and development of invasive malignancy by TP53 mutation [4], a smaller number (~15%) develop as a consequence of mismatch repair (MMR) deficiency. These tumours are characterised by high frequency microsatellite instability (MSI), proximal colonic distribution, poor differentiation, mucinous appearance, and lymphocytic infiltration [5]. Chromosomally unstable tumours tend to be aneuploid and have no site predilection [6]

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Conclusion