High Thymidylate Synthase Expression in Colorectal Cancer with Microsatellite Instability: Implications for Chemotherapeutic Strategies

Abstract

Colon cancers displaying microsatellite instability (MSI) are clinically less aggressive. Based on in vitro studies and recent clinical data, cancers displaying MSI do not respond to 5-fluorouracil (5-FU). The reasons why MSI tumors are clinically less aggressive and do not respond to 5-FUb ased therapies have not been fully elucidated. Purpose: We investigated biomolecular markers in an attempt to explain the different clinical behavior and chemotherapeutic responses of MSI and non-MSI colon cancers. Experimental Design: One hundred ninety-two sporadic colon cancers were tested for MSI with five mononucleotide markers and methylation of the hMLH1promoter. Slides were stained for thymidylate synthase (TS), p53, MDM2, p21, h-catenin, vascular endothelial growth factor, hMLH1, hMSH2, and hMSH6.Tumors were regarded as having wild-type, functional p53 (Fp53) if reduced expression of p53 and positive MDM2 and p21 WAF1/CIP1 expressions were found. Results: Of the cases, 12.5% were MSI-H (at least two markers mutated). Of MSI-H cases, 83.3% were characterized by a complete loss of at least one of the mismatch repair proteins, in particular loss of hMLH1by promoter hypermethylation. MSI-H colon cancers showed higher expression of TS compared with MSS (no mutated markers)/MSI-L (one mutated marker) colon cancers (66.6% for MSI-H versus 14.8 % MSS/MSI-L; P < 0.0001); 20.8% of MSI-H cases showed high expression of the vascular endothelial growth factor, compared with 45.8% MSS/ MSI-L colon cancers (P = 0.0005); 45.8% MSI-H cases had Fp53 compared 11.9% MSS/MSI-L cases (P < 0.0001).Conclusions: About 12% of colon cancers display MSI mostly due to lack of hMLH1 resulting from promoter hypermethylation. These tumors have high expression of TS and retain fully functional p53 system. Thus, these data suggest why sporadic hMLH1-defective colon cancers often do not respond to 5-FU.

Combination of p53 expression and p21 loss has an independent prognostic impact on sporadic colorectal cancer

“…We observed an expression of p53 in 63% of the colorectal carcinomas which is in line with previous studies, where a range of 40 to 81% p53 positivity was found (10)(11)(12)(13). This wide range depends on different techniques used in these studies, such as different antibodies, scoring systems, cutoff-values and study populations.…”

“…Further, we found a significant association of p21-negative carcinomas and rectal localization. Ricciardiello et al (10) reported an enhanced p21 expression in the right colon. Apart from these studies, data on p21 and its relationship to clinical and pathological findings are rare.…”

Thymidylate synthase and microsatellite instability in colorectal cancer: Implications for disease free survival, treatment response and survival with metastases

“…Importantly, our study shows, for the first time the relationship between these two key molecules in a group of patients with locally advanced or metastatic CRC receiving similar treatment. Other studies have only hypothesized their relationship with treatment, whereas with the clinical data available in this study we have been able to assess this relationship [8]. In the present study, we calculated a variety of indices to measure this TS-MMR co-expression, and these were related to different clinical variables, response to treatment and tested as predictors of disease outcome (DSF, DSS and survival with metastases).…”

“…This is the first study to establish such a direct relationship between hMLH1 and TS. Previously, Ricciardiello et al reported an inverse correlation between hMLH1 and TS [8], whereas the other two published studies could not establish any relation between MMR and TS [6,8].…”

“…They also showed that the MSI status and TS expression were unrelated, and was of no prognostic significance, implicating that TS levels cannot explain the therapeutic resistance to 5-FU reported in tumours with high frequency of MSI [7]. The second study by Ricciardiello et al examined a group of patients with Dukes' B, C and D and reported that tumours with MSI and defective MMR system show high expression of TS, indicating that also the tumours with high levels of TS do respond to chemotherapeutic agents [8]. Popat et al showed no relationship between MMR status and TS in a group of patients with stage A, B and C [9].…”