%0 Journal Article
%T Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expression
%A S£¿ren A Jensen
%A Ben Vainer
%A Mogens Kruh£¿ffer
%A Jens B S£¿rensen
%J BMC Cancer
%D 2009
%I BioMed Central
%R 10.1186/1471-2407-9-25
%X MSI 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.MSI 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¨C0.7; P = 0.0007) and death (HR = 0.4; 95% CI: 0.2¨C0.9; 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).The 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.Colorectal cancer is the fourth most common malignant tumor in Western Europe and Northern America affecting 7% of the population and ranks as the second leading cause of cancer-related mortality [1].The majority of colorectal cancers display aneuploidy appearing as chromosomal anomalies, whereas the remainder that constitutes 15¨C20% of these cancers is characterized by microsatellite instability (MSI) [2-6].Microsatellites are DNA sequences in which a short motif of 1¨C5 nucleotides are tandemly repeated ten to hundred times. 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 o
%U http://www.biomedcentral.com/1471-2407/9/25