Low thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase mRNA expression correlate with prolonged survival in resected non-small-cell lung cancer.
BACKGROUND
Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are key enzymes in the 5-fluorouracil (5-FU) pathway. The aim of this study was to investigate the mRNA expression of TS, TP, and DPD in tumor and nontumor lung tissue of patients with NSCLC and to determine the potential of these genes as molecular biomarkers.


METHODS
The TS, TP, and DPD mRNA expression was analyzed in tumor and nontumor tissue of 91 patients with NSCLC by quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) with β-actin as the internal control. All tumors were R0 resected. The median follow-up was 85.9 months.


RESULTS
The mRNA expression of TS, TP, and DPD was detectable in both tumor and nontumor tissue. Tumor TP (tTP) seems to correlate with tumor TS (tTS) and tumor DPD (tDPD) mRNA expression, but no correlation in the mRNA expression of tTS and tDPD was found. The TS and TP mRNA expression levels were significantly associated with patient prognosis. The 5-year survival probability was 58.7% (TS), and 59.6% (TP) for patients with a low TS and TP mRNA expression and 33.4% (TS), and 31.8% (TP) for patients with a high mRNA expression (P = .04 [TS]; P = .03 [TP]; log-rank). The probability of survival was significantly different among patients with no and any 1 highly expressed gene compared with patients with any 2 or more of the 3 investigated genes highly expressed (P = .012).


CONCLUSIONS
High TS, TP, and DPD mRNA expression are biomarkers for a more severe malign NSCLC biology. Quantitation of the mRNA expression of these genes seems to be helpful in differing patients with unequal malign tumor entities and therefore possibly helpful in selecting tailored additional therapies to control the disease.
Grimminger
Peter P
PP
Department of General, Visceral and Tumor Surgery, University of Cologne, Germany. pgrimminger@gmail.com
Schneider
Paul M
PM
Metzger
Ralf
R
Vallböhmer
Daniel
D
Hölscher
Arnulf H
AH
Danenberg
Peter V
PV
Brabender
Jan
J
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000401:mortality* / Q000601:surgery; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality* / Q000601:surgery; D008297:Male; D011379:Prognosis; D012333:RNA, Messenger / Q000302:isolation & purification; D018709:Statistics, Nonparametric; D015996:Survival Rate; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil