Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability.
BACKGROUND
5-Fluorouracil (5-FU) is the most commonly used therapeutic agent for colon cancer treatment. Several studies have evaluated in patients with colon cancer, either the role of genes involved in the 5-FU pathway, such as thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) or the role of microsatellite instability (MSI) as prognostic or predictive markers for adjuvant chemotherapy efficacy, with discordant results. In this study we investigated the combined effect of TS, TP, DPD mRNA expression and MSI status in primary tumors of patients with colon cancer, all treated with 5-FU adjuvant therapy.


METHODS
TS, TP and DPD expression levels were investigated by real-time quantitative RT-PCR on RNA extracts from formalin-fixed and paraffin-embedded tissues of 55 patients with colon adenocarcinoma. In the same case study MSI status was assessed on DNA extracts.


RESULTS
A higher TS expression was significantly associated with a longer survival for patients with cancers of stage II (P < 0.01), but not for those with stage III (P = 0.68). In addition, in multivariate analysis, a higher TS expression was significantly associated with a decreased risk of death (HR 0.13, 95% CI 0.03-0.59, P < 0.01), while the MSI status did not have effects on patients' survival.


CONCLUSIONS
This retrospective investigation suggests that TS gene expression at mRNA level can be a useful marker of better survival in patients (especially of those with cancers of stage II) receiving 5-FU adjuvant chemotherapy, independently of the MSI status.
Donada
Marisa
M
ACADEM Department, Cattinara Hospital, University of Trieste, Surgical Pathology Bldg, Strada di Fiume 447, 34149 Trieste, Italy.
Bonin
Serena
S
Nardon
Ermanno
E
De Pellegrin
Alessandro
A
Decorti
Giuliana
G
Stanta
Giorgio
G
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil
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