Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expressionReport as inadecuate




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BMC Cancer

, 9:25

First Online: 20 January 2009Received: 31 July 2008Accepted: 20 January 2009DOI: 10.1186-1471-2407-9-25

Cite this article as: Jensen, S.A., Vainer, B., Kruhøffer, M. et al. BMC Cancer 2009 9: 25. 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.

AbbreviationsMSIMicrosatellite instability

MSSmicrosatellite stability

MMRmismatch repair

TSthymidylate synthase

DPDdihydropyrimidine dehydrogenase.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-9-25 contains supplementary material, which is available to authorized users.

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Author: Søren A Jensen - Ben Vainer - Mogens Kruhøffer - Jens B Sørensen

Source: https://link.springer.com/







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