Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expression

Jens B Sørensen,Ben Vainer,Søren A Jensen,Mogens Kruhøffer

doi:10.1186/1471-2407-9-25

Abstract

BackgroundMicrosatellite instability (MSI) refers to mutations in short motifs of tandemly repeated nucleotides resulting from replication errors and deficient mismatch repair (MMR). Colorectal cancer with MSI has characteristic biology and chemosensitivity, however the molecular basis remains unclarified. The association of MSI and MMR status with outcome and with thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer were evaluated.MethodsMSI in five reference loci, MMR enzymes (hMSH2, hMSH6, hMLH1 and hPMS2), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression were assessed in paraffin embedded tumor specimens, and associated with outcome in 340 consecutive patients completely resected for colorectal cancer stages II-IV and subsequently receiving adjuvant 5-fluorouracil therapy.ResultsMSI was found in 43 (13.8%) tumors. Absence of repair protein expression was assessed in 52 (17.0%) tumors, which had primarily lost hMLH1 in 39 (12.7%), hMSH2 in 5 (1.6%), and hMSH6 in 8 (2.6%) tumors. In multivariate analysis MSI (instable) compared to MSS (stable) tumors were significantly associated with lower risk of recurrence (hazard ratio (HR) = 0.3; 95% CI: 0.2–0.7; P = 0.0007) and death (HR = 0.4; 95% CI: 0.2–0.9; P = 0.02) independently of the TS and DPD expressions. A direct relationship between MSI and TS intensity (P = 0.001) was found, while there was no significant association with DPD intensity (P = 0.1).ConclusionThe favourable outcome of MSI colorectal carcinomas is ascribed mainly to the tumor biology and to a lesser extent to antitumor response to 5-fluorouracil therapy. There is no evidence that differential TS or DPD expression may account for these outcome characteristics.

Highlights

Microsatellite instability (MSI) refers to mutations in short motifs of tandemly repeated nucleotides resulting from replication errors and deficient mismatch repair (MMR)
The majority of colorectal cancers display aneuploidy appearing as chromosomal anomalies, whereas the remainder that constitutes 15–20% of these cancers is characterized by microsatellite instability (MSI) [2,3,4,5,6]
In the remainders analyses failed for technical reasons partly because of DNA degradation in tumor necrosis

Summary

Introduction

Microsatellite instability (MSI) refers to mutations in short motifs of tandemly repeated nucleotides resulting from replication errors and deficient mismatch repair (MMR). Microsatellites are prone to mutation during replication due to transient split of the two helical strands and slippage of the DNA polymerase complex at reannealing, which generate an insertion or deletion loop depending on slippage direction. Unless such mismatch is corrected, the loss or gain of repeated units on the daughter strand results in length variation termed microsatellite instability (MSI) [7]. Upon assemblage this complex interact with another heterodimeric complex, composed of hMLH1 and hPMS2 [8]

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