title: Thymidilate synthase expression predicts longer survival in patients with stage II colon cancer treated with 5-flurouracil independently of microsatellite instability.
abstract: 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.
authors.affiliation: ACADEM Department, Cattinara Hospital, University of Trieste, Surgical Pathology Bldg, Strada di Fiume 447, 34149 Trieste, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Donada
authors.forename: Serena
authors.initials: S
authors.lastname: Bonin
authors.forename: Ermanno
authors.initials: E
authors.lastname: Nardon
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Pellegrin
authors.forename: Giuliana
authors.initials: G
authors.lastname: Decorti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stanta
mesh_terms: 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
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil
references.citation: Int J Colorectal Dis. 2006 Apr;21(3):238-47
references.pmid: 16132996
references.citation: Cancer Lett. 2004 Feb 10;204(1):97-104
references.pmid: 14744539
references.citation: Dig Dis Sci. 2008 May;53(5):1289-96
references.pmid: 17934851
references.citation: Biochem Biophys Res Commun. 1992 May 15;184(3):1311-6
references.pmid: 1590793
references.citation: J Clin Oncol. 2006 Jan 10;24(2):241-51
references.pmid: 16330668
references.citation: Acta Derm Venereol. 2004;84(2):106-10
references.pmid: 15206688
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Clin Cancer Res. 1998 Oct;4(10):2371-6
references.pmid: 9796967
references.citation: Eur J Surg Oncol. 2005 Oct;31(8):863-8
references.pmid: 15923105
references.citation: Methods Mol Biol. 1998;86:23-6
references.pmid: 9664448
references.citation: Gastroenterology. 2000 Oct;119(4):921-8
references.pmid: 11040179
references.citation: Int J Cancer. 2007 Feb 1;120(3):694-701
references.pmid: 17096352
references.citation: Oncology. 2006;70(5):366-77
references.pmid: 17179731
references.citation: J Clin Oncol. 2004 Feb 1;22(3):529-36
references.pmid: 14752076
references.citation: Cancer Res. 2004 Aug 1;64(15):5245-50
references.pmid: 15289330
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: J Clin Oncol. 2005 Jan 20;23(3):609-18
references.pmid: 15659508
references.citation: Exp Mol Pathol. 2009 Oct;87(2):146-51
references.pmid: 19619529
references.citation: J Gastroenterol. 2005 Feb;40(2):143-7
references.pmid: 15770397
references.citation: Cancer Res. 2007 Jan 1;67(1):41-56
references.pmid: 17210682
references.citation: Cancer Res. 1998 Aug 1;58(15):3455-60
references.pmid: 9699680
references.citation: Oncol Rep. 2005 Jul;14(1):241-9
references.pmid: 15944796
references.citation: Ann Clin Biochem. 2003 Jan;40(Pt 1):41-5
references.pmid: 12542909
references.citation: Clin Cancer Res. 2005 Jun 1;11(11):4234-40
references.pmid: 15930362
references.citation: Ann Oncol. 2008 May;19(5):915-9
references.pmid: 18245778
references.citation: J Clin Oncol. 2004 Aug 15;22(16):3408-19
references.pmid: 15199089
references.citation: Gastroenterol Clin North Am. 2008 Mar;37(1):25-46, v
references.pmid: 18313538
references.citation: BMC Cancer. 2009 Jan 20;9:25
references.pmid: 19154585
references.citation: Ann Oncol. 2006 Dec;17(12):1810-7
references.pmid: 16971666
references.citation: Nucleic Acids Symp Ser (Oxf). 2008;(52):629
references.pmid: 18776537
references.citation: Clin Cancer Res. 2009 Dec 15;15(24):7642-7651
references.pmid: 19996206
references.citation: Dis Markers. 2004;20(4-5):225-36
references.pmid: 15528788
references.citation: J Clin Oncol. 2002 Apr 1;20(7):1721-8
references.pmid: 11919227
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: N Engl J Med. 2003 Jul 17;349(3):247-57
references.pmid: 12867608
references.citation: J Natl Cancer Inst. 1996 Aug 21;88(16):1110-7
references.pmid: 8757190
references.citation: Gastroenterology. 2002 Dec;123(6):1804-11
references.pmid: 12454837
references.citation: Br J Surg. 2006 Apr;93(4):395-406
references.pmid: 16555243
references.citation: Clin Cancer Res. 2006 May 1;12(9):2738-44
references.pmid: 16675565
references.citation: Ann Surg Oncol. 2006 Jun;13(6):887-98
references.pmid: 16614880