Thymidylate synthase in situ protein expression and survival in stage I nonsmall-cell lung cancer

Cancer. 2008 Jun 15;112(12):2765-73. doi: 10.1002/cncr.23491.


Background: Thymidylate synthase (TS) is important for maintenance of the intracellular thymidine pool, which is crucial for DNA synthesis and repair. TS messenger RNA and protein levels are predictive of response to 5-fluorouracil-containing therapy for patients with colorectal cancer and gastric cancer. High levels of expression of 2 other genes important in DNA synthesis and repair, RRM1 and ERCC1, are prognostic of survival in early stage nonsmall-cell lung cancer (NSCLC) patients. We hypothesized that intratumoral TS expression would be prognostic of outcome in stage I NSCLC.

Methods: Cytoplasmic tumoral TS was determined by automated in situ protein quantification (AQUA) in 160 patients with completely resected NSCLC that had not received chemotherapy or radiation. It was also determined by real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in 85 similar patients. The 2 datasets were partially overlapping (N=32). The optimal cutpoint was determined by the maximal log-rank method with adjustment of the P-values for multiple looks.

Results: TS protein expression was significantly associated with patient survival (P=.0013, adjusted P=.034). The optimal cutpoint was at the 25% percentile; the group with low expression (<or=57.02) had a median overall survival (OS) of 51.7 months, and the high expression group (>57.02) had a median OS of 81.3 months. TS mRNA expression was not significantly associated with patient survival or TS protein expression. In a multivariate analysis adjusting for tumor stage, TS remained significantly prognostic of survival (P=.0013, adjusted P=.032).

Conclusions: In situ cytoplasmic TS protein expression in tumors of patients with resected stage I NSCLC is a clinically important determinant of survival.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / metabolism
  • Biomarkers, Tumor / analysis
  • Carcinoma, Large Cell / metabolism
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • DNA-Binding Proteins / metabolism
  • Endonucleases / metabolism
  • Female
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Male
  • Neoplasms, Squamous Cell / metabolism
  • Prognosis
  • RNA, Messenger / metabolism
  • Ribonucleoside Diphosphate Reductase
  • Smoking
  • Survival Analysis
  • Thymidylate Synthase / metabolism*
  • Tumor Suppressor Proteins / metabolism


  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • RRM1 protein, human
  • Ribonucleoside Diphosphate Reductase
  • Thymidylate Synthase
  • ERCC1 protein, human
  • Endonucleases