Abstract 5249: Analysis of gene expression levels associating with metabolism of 5-fluorouracil and folate in primary colorectal cancer and corresponding synchronous or metachronous liver metastasis

Abstract

Abstract Background Gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) have been shown to be associated with response to 5-fluorouracil-based therapies. Folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH) and dihydrofolate reductase (DHFR) are associated with folate metabolism which regulates intracellular folate level. Analyzing these gene expression levels in liver metastases is important to obtain the prediction of therapy, however, only surgical specimens of the primary tumor are readily available for analysis in many cases. Our aim is to determine how TS, DPD, TP, OPRT, FPGS, GGH and DHFR gene expression levels in primary colorectal cancer (CRC) are related to those in liver metastases. Methods Formalin-fixed, paraffin-embedded tumor specimens from 50 pairs of primary CRC and corresponding liver metastases, including 30 synchronous and 20 metachronous metastases, were dissected by using laser-captured microdissection. Total RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target genes and internal reference gene, beta-2-microglobulin, was performed using real-time RT-PCR. Results Significant difference was seen between mRNA expression levels of TS, DPD, FPGS and DHFR in primary tumor and those in corresponding synchronous liver metastases (median value: TS 1.18 vs. 0.05; p<0.0001, DPD 0.18 vs.0.05; p<0.0001, FPGS 0.07 vs. 0.02; p=0.0005, DHFR 0.31 vs. 0.03; p<0.0001), TS, DPD, TP, OPRT, FPGS and DHFR in primary tumor and those in corresponding metachronous liver metastases (TS 0.23 vs. 0.06; p<0.0001, DPD .0.31 vs. 0.03; p<0.0001, TP 0.21 vs. 0.14, p=0.021, OPRT 0.35 vs. 0.17; p=0.016, FPGS 0.11 vs. 0.04; p=0.0003, DHFR 0.41 vs. 0.03, p<0.0001). When matched tissue sets were compared on an individual basis, there was a significant correlation for TP, OPRT and FPGS mRNA expression between primary tumor and corresponding synchronous liver metastases (TP rs=0.64; p=0.018, OPRT rs=0.62; p=0.006, FPGS rs=0.51; p=0.004), DPD and GGH in primary tumor and corresponding metachronous liver metastases (DPD rs=0.54; p=0.014, GGH rs=0.59; p=0.007). Conclusion A good prediction of TP, OPRT and FPGS mRNA levels in synchronous liver metastases as well as DPD and GGH mRNA levels in metachronous liver metastasis can be obtained by measuring those of primary CRC, although no correlation was seen for other genes. We are currently investigating more number of cases and genes related with sensitivity to antitumor drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5249. doi:10.1158/1538-7445.AM2011-5249