title: Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers.
abstract: Thymidylate synthase (TS) intratumoural expression may be a prognostic marker and predict outcome of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer patients. The TS gene promoter enhancer region contains two different polymorphisms which can influence TS mRNA transcriptional and translational efficiency: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism (SNP), G > C, within the second repeat of the 3R alleles. We studied the relationship between tumoural TS mRNA expression levels and TS gene polymorphisms in the colonic mucosa of 48 colorectal cancer patients. The 3R/3R genotype was characterised by higher TS mRNA levels in the tumour than the 2R/2R-2R/3R genotypes (P = 0.071). Regarding the relationship with the SNP polymorphism, a statistically significant difference in TS gene expression between the 3RG/3RG genotype and 2R/2R-2R/3RC-2R/3RG genotype subset was observed (P = 0.017). No statistically significant correlation was observed between experimental data and baseline clinical-pathological characteristics as well as clinical outcome in the relatively small patient series investigated. This is the first study reporting an association between the TS intra-repeat SNP and gene expression levels in colorectal cancer patients. These results suggest that in 3R/3R patients, the G > C polymorphism may be an important factor in determining TS mRNA expression levels, and warrant further investigation of the role of TS promoter polymorphisms as predictors of sensitivity to 5-FU-based chemotherapy in larger case series.
authors.affiliation: Dipartimento di Farmacologia, Unità di Chemioterapia, Università degli Studi di Firenze, viale Pieraccini, 6, 50139, Firenze, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Morganti
authors.forename: Monica
authors.initials: M
authors.lastname: Ciantelli
authors.forename: Beatrice
authors.initials: B
authors.lastname: Giglioni
authors.forename: Anna L
authors.initials: AL
authors.lastname: Putignano
authors.forename: Stefania
authors.initials: S
authors.lastname: Nobili
authors.forename: Laura
authors.initials: L
authors.lastname: Papi
authors.forename: Ida
authors.initials: I
authors.lastname: Landini
authors.forename: Cristina
authors.initials: C
authors.lastname: Napoli
authors.forename: Rosa
authors.initials: R
authors.lastname: Valanzano
authors.forename: Fabio
authors.initials: F
authors.lastname: Cianchi
authors.forename: Vieri
authors.initials: V
authors.lastname: Boddi
authors.forename: Francesco
authors.initials: F
authors.lastname: Tonelli
authors.forename: Camillo
authors.initials: C
authors.lastname: Cortesini
authors.forename: Teresita
authors.initials: T
authors.lastname: Mazzei
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D013940:Thymidylate Synthase