title: Associations between polymorphisms in the thymidylate synthase gene, the expression of thymidylate synthase mRNA and the microsatellite instability phenotype of colorectal cancer.
abstract: Microsatellite instability (MSI) is a characteristic feature of up to 15% of colorectal cancers (CRC) and is associated with better response to adjuvant chemotherapy with 5-fluorouracil (5-FU). In this study we have investigated the association between the MSI status and the mRNA expression as well as the polymorphisms of the cellular target of 5-FU therapy, thymidylate synthase. Polymorphisms in the 3'- and the 5'-UTR of the TS gene were determined by a PCR assay in 53 colorectal cancer tissues. TS mRNA was quantified by real-time RT-PCR. Data were correlated with the MSI phenotype. There was neither a significant correlation between the polymorphisms in the TS gene and the MSI phenotype nor between the mRNA expression and MSI status. CRC with a 3R/3R or 2R/3R genotype showed a significantly higher TS mRNA expression than those with 2R/2R genotype (p=0.001 and p=0.026, respectively). No association was seen between the polymorphism of the 3'-UTR and mRNA expression. From our results, we conclude that there is no association between MSI status and TS expression. Samples containing the 3R/3R or 2R/3R genotype of TS seem to have higher mRNA levels perhaps due to a higher mRNA stability. Polymorphic variants of the 3'-UTR do not influence the TS mRNA level. Genotyping of the 5'-UTR and quantitation of TS mRNA levels might serve as predictors for the response to 5-FU based chemotherapy.
authors.affiliation: Department of Pathology, University of Bonn, D-53105 Bonn, Germany. sabine.merkelbach-bruse@ukb.uni-bonn.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.forename: Volkmar
authors.initials: V
authors.lastname: Hans
authors.forename: Micaela
authors.initials: M
authors.lastname: Mathiak
authors.forename: Rosario
authors.initials: R
authors.lastname: Sanguedolce
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Farzad
authors.initials: F
authors.lastname: Houshdaran
authors.forename: Lucia
authors.initials: L
authors.lastname: Gullotti
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil