title: Overexpression of thymidylate synthetase confers an independent prognostic indicator in nasopharyngeal carcinoma.
abstract: Data mining on public domain identified that thymidylate synthetase (TYMS) and dihydrofolate reductase (DHFR) transcripts were significantly higher expressed in nasopharyngeal carcinoma (NPC). In the folate pathway, TYMS catalyzes the methylation of deoxyuridylate to deoxythymidylate using 5,10-methylenetetrahydrofolate [5,10-CH2=THF, derived from tetrahydrofolate (THF)], as a cofactor. This function maintains the thymidine-5-prime monophosphate pool critical for DNA replication and repair and, THF is generated from dihydrofolate (DHF) through the activity of DHFR. Immunoexpression of TYMS and DHFR were retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The outcome was correlated with clinicopathological features and patient survivals. Results indicated that high TYMS (50%) expressions were correlated with primary tumor (p=0.008) and AJCC stage (p=0.006), and high DHFR (50%) expression were correlated with nodal status (p=0.039) and AJCC stage (p=0.029) (7th American Joint Committee on Cancer), respectively. In multivariate analyses, high TYMS expression emerged as an independent prognosticator for worse disease-specific survival (p<0.001), distal metastasis-free survival (p=0.002) and local recurrence-free survival (p<0.001), along with AJCC stage. Therefore, TYMS expression is common and associated with adverse prognosticators and might confer tumor aggressiveness through dysregulation of the nucleotide biosynthetic process.
authors.affiliation: Department of Radiation Oncology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Sung-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Tzu-Ju
authors.initials: TJ
authors.lastname: Chen
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lin
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.forename: Han-Ping
authors.initials: HP
authors.lastname: Hsu
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.forename: Yow-Ling
authors.initials: YL
authors.lastname: Shiue
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002277:Carcinoma; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D011237:Predictive Value of Tests; D011379:Prognosis; D012016:Reference Values; D012189:Retrospective Studies; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
keywords: Nasopharyngeal carcinoma; Survival; TYMS; Thymidylate synthetase