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Anticancer Res. 2014 Sep;34(9):4949-62.

Prognostic markers in early-stage colorectal cancer: significance of TYMS mRNA expression.

Author information

1
Fourth Department of Internal Medicine, Attikon University Hospital, Athens, Greece akoumari@yahoo.com.
2
First Propaedeutic Department of Surgery, AHEPA Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
3
Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
4
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
5
STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
6
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
7
Department of Pathology, Metaxas Cancer Hospital, Piraeus, Greece.
8
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
9
Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
10
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
11
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.

Abstract

BACKGROUND:

Several studies have recently indicated the prognostic or predictive role of several biomarkers in colorectal cancer. We sought to investigate the prognostic value of prostaglandin synthase 2 (PTGS2), cyclooxygenase 2 (COX2), thymidylate synthetase (TYMS), thymidine phosphorylase (TYMP), dihydropyrimidine dehydrogenase (DPYD) and topoisomerase I (TOPO1) in colorectal cancer patients treated with 5-FU-based regimens, such as De Gramont and FOLFOX in the adjuvant setting.

MATERIALS AND METHODS:

In total, 96 formalin-fixed paraffin-embedded and 30 fresh-frozen tumor tissue samples were evaluated using immunohistochemistry, quantitative reverse transcription-polymerase chain reaction and microarray gene expression profiling, respectively.

RESULTS:

The majority of tumors exhibited protein overexpression of COX2 (69%), TYMS (75%) and TOPO1 (75%). There was a significant association of TYMP protein expression with T classification, gender and stage (p=0.040, p=0.041 and p=0.011, respectively). TOPO1 protein expression was correlated with TOPO1 mRNA expression and was positively associated with stage (p=0.002) and lymph node infiltration (p=0.004). In univariate analysis, patients with high TYMS mRNA expression were shown to have a significantly lower risk for progression and death (Wald's p=0.030 and p=0.015, respectively). However, in multivariate analysis, only a trend for decreased risk for death was shown in patients with high TYMS mRNA expression (Wald's p=0.083), while patients with high PTGS2 mRNA expression had a trend for lower risk for progression (p=0.064). Using supervised hierarchical clustering, based on the expression in fresh-frozen tumor tissue of PTGS2, TYMS, TYMP and DPYD, our 30 patients were separated into two clusters. One of the clusters was enriched with patients with infiltrated lymph nodes (p<0.05), suggesting that these genes might have an impact on the tumor's ability to metastasize.

CONCLUSION:

These findings indicate a possible prognostic role of TYMS mRNA expression and highlight a cluster of genes associated with nodal metastases that warrant further investigation in a larger cohort of patients with colorectal cancer treated with 5-FU-based adjuvant chemotherapy.

KEYWORDS:

5-FU-based adjuvant chemotherapy; COX2; DPYD; PTGS2; TOPO1; TYMP; TYMS; hierarchical clustering; stage II colorectal cancer; stage III colorectal cancer

PMID:
25202077
[Indexed for MEDLINE]

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