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

Four 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.244 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).Relationships 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.Colorectal cancer (CRC) is one of the commonest malignancies of developed countries [1], with approximately 19,000 and 160,000 new cases in the UK and US, respectively, each year, and around 500,000 new cases world-wide [2,3]. 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]. Additionally, these tumours tend to retain the native diploid state [5]. By contrast, chromosomally uns