5-fluorouracil related gene expression levels in primary colorectal cancer and corresponding liver metastases

Abstract

3568 Background: The most commonly used chemotherapeutic drug for colorectal cancer (CRC) is 5-fluorouracil (5-FU). Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyl transpherase (OPRT) are involved in the metabolic pathway of 5-FU and have been shown in several studies to be associated with response to 5-FU-based therapies. Since liver metastases are the main cause of death for most of CRC patients, it is reasonable to expect that measurement of these gene expression levels in liver metastases would provide the best prediction of therapy benefit, but in most cases, only biopsies of the patient’s primary tumor are readily available for analysis. Our aim was to determine how TS, DPD, TP, and OPRT gene expression levels in primary CRC were related to those in liver metastases. Methods: Thirty-one pairs of primary CRC and corresponding liver metastases were analyzed. (18 males and 13 females: Median age 66 (range 45–85)). Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR (Taqman PCR). Results: No significant difference was seen between median mRNA expression levels of TS, DPD, TP, and OPRT in primary cancer and those in corresponding liver metastases (Median value: TS 1.48 vs. 1.43; p=0.92, DPD 0.19 vs.0.12; p=0.10, TP 1.20 vs. 0.98; p=0.39, OPRT 1.17 vs. 0.95; p=0.10, Wilcoxon signed rank test). When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs=0.52, p=0.0026, Spearman rank correlation coefficient). However, no correlation was seen between matched sets for DPD, TP, or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs=0.38, p=0.03) and liver metastases (rs=0.72, p<0.0001). Conclusions: A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP, and OPRT. No significant financial relationships to disclose.