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Association of microsatellite instability with thymidylate synthase and dihydropyrimidine dehydrogenase expression in colorectal cancer

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Background.

Microsatellite instability (MSI) refers to mutations in short motifs of tandemly repeated nucleotides that result from replication errors and deficient mismatch repair (MMR). Colorectal cancer with MSI has characteristic biology and chemosensitivity, however the molecular basis for this remains unclarified. This study aimed to evaluate the association of MSI and MMR status, with outcome and with thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression in colorectal cancer. Methods.

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 tumour specimens, and associated with outcome in 336 consecutive patients who were completely resected for colorectal cancer stages II-IV and subsequently adjuvantly treated with 5-fluorouracil. Results.

In Cox multivariate analysis patients with MSI-H (high frequency) tumours compared to MSS/MSI-L (stable/ low frequency) tumours were significantly associated with lower risk of recurrence (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), adjusted for the independent prognostic impact of disease stage (P=0.0001), vascular invasion (P=0.02), perineural invasion (P=0.05), and ileus (P=0.0002). Similarly, tumors deficient of any MMR protein expression compared to MMR competent tumors were significantly associated with lower risk of recurrence (HR=0.6; 95% CI: 0.4–0.9 P=0.02) and death (HR=0.6; 95% CI: 0.4–1.0; P=0.05), independently of disease stage (P=0.001), perineural invasion (P=0.05), vascular invasion (P=0.04), and ileus (P=0.001).

A direct relationship between MSI-H and TS intensity (P=0.001) appeared, while there was no significant association with DPD intensity (P=0.1). Also to predict outcome interaction with MSI status were statistically significant for TS for recurrence (P=0.002) and death (P=0.02), and non significant for DPD for recurrence (P=0.5) and death (P=0.9). Conclusions.

Characterizing colorectal carcinomas by MSI and MMR expression may disclose a subset of patients with significantly favourable outcome. This may be utilized in selection of patients for treatment approaches and for decision on follow-up programs. It was suggested that MSI might influence outcome through interference with TS expression.
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Document Type: Abstract

Affiliations: 1: Pathologisk afd., Rigshospitalet, Kbh. 2: Klin. Biokem. afd., Skejby, Aarhus, Danmark 3: Onkologisk

Publication date: 2008-05-01

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