title: Thymidylate synthase expression pattern is a prognostic factor in patients of colorectal cancer treated with 5-fluorouracil.
abstract: High intratumoral expression of thymidylate synthase (TS) has been reported as a factor of poor prognosis in patients with advanced colorectal cancer (CRC), but such association is unclear in some studies. Also, TS has been stated as a typical cytosolic enzyme, but nuclear location has been occasionally reported, and data on the clinical meaning of TS intracellular location are scarce. A retrospective study was performed in paraffin-embedded sections of primary tumor from 77 CRC patients treated with surgical resection and adjuvant 5-FU-based chemotherapy. TS levels and expression patterns were determined by immunohistochemistry (IHQ) using TS-106 antibody. Qualitative and quantitative variables were compared respectively by chi2 and Kruskal-Wallis tests; overall survival (OS) and disease-free survival (DFS) were analyzed with the Kaplan-Meier method and compared using the log-rank and Wilcoxon tests. TS was cytoplasmic in 27.1% of positive tumors and both, nuclear and cytoplasmic in 72.9%; specimens from seven patients (9.1%) lacked TS expression. TS levels were high in 21.6% of tumors with nuclear expression and low in 5.6%, whereas 68.4% of cytoplasmic ones showed low immunostaining intensity (p=0.02); cytoplasmic pattern was also associated to longer OS (p<0.009) and DFS (p=0.003). In patients with nuclear expression, low TS expression was associated to shorter OS (p<0.003) and DFS (p<0.04). These results indicate that, in our study, TS immunostaining patterns were related with OS and DFS, the best prognostic corresponding to cytoplasmic one, and, within the subset of patients with nuclear expression, low TS levels were associated to worse clinical outcome.
authors.affiliation: Department of Pathology, Hospital Universitario de la Princesa, Universidad Autónoma, Madrid, Spain.
authors.forename: María-Encarnación
authors.initials: ME
authors.lastname: Fernández-Contreras
authors.forename: Beatriz
authors.initials: B
authors.lastname: Jiménez De Ayala
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: García De Paredes
authors.forename: Amalia
authors.initials: A
authors.lastname: Velasco
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Majano
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Carlos
authors.initials: C
authors.lastname: Gamallo
mesh_terms: D000368:Aged; D002467:Cell Nucleus / Q000201:enzymology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D005260:Female; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013940:Thymidylate Synthase / Q000032:analysis*
chemical_list: D013940:Thymidylate Synthase; D005472:Fluorouracil