Influence of thymidylate synthase gene polymorphisms on the survival of colorectal cancer patients receiving adjuvant 5-fluorouracil.
The present study aimed to prospectively investigate the influence of thymidylate synthase (TS) polymorphisms (5'-TSER, 3'-TSUTR) on the disease-free survival (DFS) and overall survival (OS) of patients with colorectal cancer (CRC) who were treated with adjuvant 5-fluorouracil (5-FU) therapy. Patients were followed up for 19+/-14 months (median+/-SD). TS genotypes were determined from the peripheral blood mononuclear cells of 166 patients by polymerase chain reaction-polyacrylamide gel electrophoresis and restriction fragment length polymorphism methods. 5'-TSER 3R homozygotes showed significantly longer DFS (P = 0.048) and OS (P = 0.009). The 5'-TSER and 3'-TSUTR genotype combination groups showed a significant difference for DFS (P = 0.039) and OS (P = 0.029). Significantly better DFS (P = 0.049) and OS (P = 0.043) were observed for 6 bp/6 bp genotypes in 5'-TSER heterozygotes (n = 80). Based on this, and on hazard ratios obtained by Cox regression analysis of the DFS of genotype-combinations, the patients were classified as belonging to prognostic groups A and B. The DFS and OS of these two groups showed a highly significant difference (P = 0.002 and 0.001). In the multivariate Cox regression model, beside tumour location, the prognostic classification (groups A and B) proved to be an independent prognostic factor. Our data suggest that those TS genotypes and their combinations (group A: 3R/3R with any 3'-TSUTR genotype and 2R/3R with 6 bp/6 bp), which have been reported earlier as having high TS expression, predict significantly longer DFS and OS. We found that a combination of germline TS polymorphisms is an independent prognostic marker in selecting CRC patients with worse prognosis, and it may be worthwhile to examine whether these patients would benefit from an alternative therapy.
Hitre
Erika
E
National Institute of Oncology, Budapest, Hungary.
Budai
Barna
B
Adleff
Vilmos
V
Czeglédi
Ferenc
F
Horváth
Zsolt
Z
Gyergyay
Fruzsina
F
Lövey
József
J
Kovács
Tibor
T
Orosz
Zsolt
Z
Láng
István
I
Kásler
Miklós
M
Kralovánszky
Judit
J
D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D013940:Thymidylate Synthase; D005472:Fluorouracil