Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors.
OBJECTIVE
The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available.


METHODS
A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU-based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry.


RESULTS
By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU.


CONCLUSIONS
This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.
Ceppi
Paolo
P
Thoracic Oncology Unit, Pathology Division, Department of Clinical and Biological Sciences, University of Torino, San Luigi Hospital, Torino, Italy. paolo.ceppi@unito.it
Volante
Marco
M
Ferrero
Anna
A
Righi
Luisella
L
Rapa
Ida
I
Rosas
Rosj
R
Berruti
Alfredo
A
Dogliotti
Luigi
L
Scagliotti
Giorgio V
GV
Papotti
Mauro
M
D000970:Antineoplastic Agents / Q000627:therapeutic use; D004067:Digestive System Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil