title: Influence of thymidylate synthase DNA polymorphisms and gender on the clinical evolution of patients with advanced colorectal cancer.
abstract: Experimental evidence has revealed that several thymidylate synthase (TS) DNA polymorphisms modulate gene expression, which, in turn is known to be down-regulated by oestrogen receptor subtypes. Consequently, this process might be influenced by female hormones. Based on these data, we investigated whether patient's gender and TS polymorphism exert an interactive effect on the clinical evolution of patients with advanced colorectal cancer (CRC) subjected to 5 fluorouracil (5FU)-based adjuvant chemotherapy. A retrospective study was carried out on paraffin-embedded sections from 81 CRC patients. A variable tandem repeat (VNTR) of 28 bp, a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp (ins1494del 6 bp) were studied. Genotyping methods were polymerase chain reaction (PCR) for VNTR, and PCR followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins1494del 6 bp. The effect of TS genotype and gender on overall and progression-free survival was assessed in univariate and multivariate (Cox regression model) tests. In male patients, the study of combined TS genotypes showed that G&6+/6+ was an adverse marker for overall (P=0.04; median: not reached) and progression-free survival (P=0.03; median: 12 months, 95% CI: 0-32.4). In the multivariate analysis, the concurrence of G&6+/6+ combination and male patients resulted in a 5.5-fold increased risk of relapse or disease progression (95% CI: 1-32.1; likelihood test P=0.004; interaction P=0.06). TS genotype did not affect survival among women. The present study supports that the effect of TS polymorphisms on the clinical evolution of advanced CRC patients is significantly influenced by gender.
authors.affiliation: Department of Gastroenterology and Hepathology, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006 Madrid, Spain. efernandezc.hlpr@salud.madrid.org
authors.forename: Maria-Encarnación
authors.initials: ME
authors.lastname: Fernández-Contreras
authors.forename: José Javier
authors.initials: JJ
authors.lastname: Sánchez-Hernández
authors.forename: Mercedes
authors.initials: M
authors.lastname: Guijarro
authors.forename: Javier P
authors.initials: JP
authors.lastname: Gisbert
authors.forename: Noa
authors.initials: N
authors.lastname: Rivas
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: García de Paredes
authors.forename: Adolfo
authors.initials: A
authors.lastname: Hinojar-Gutiérrez
authors.forename: Carlos
authors.initials: C
authors.lastname: Gamallo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013940:Thymidylate Synthase / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil