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Analysis of predictive biomarker and analysis of correlations between toxicities and SNPs that can be related to pharmacokinetics, in trifluridine/tipiracil hydrochloride therapy for previously fluoropyrimidine-treated elderly patients with unresectable or recurrent colorectal cancer

ABSTRACT: Interventions: Nucleic acid from tumor tissues and serum SNPs Primary outcome(s): 1. Tissue biomarkers including mutation, gene expression, and DNA methylation that correlate with efficacy from trifluridine/tipiracil hydrochloride therapy 2. Serum biomarkers including mutation, gene expression, and DNA methylation that correlate with efficacy from trifluridine/tipiracil hydrochloride therapy 3. SNPs that correlate with toxicities from trifluridine/tipiracil hydrochloride therapy Study Design: Single arm Non-randomized

DISEASE(S): Colorectal Cancer

PROVIDER: 2637006 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Aberrant DNA methylation, one of the major epigenetic alterations in cancer, has been reported to accumulate in a subset of colorectal cancer (CRC), so-called CpG island methylator phenotype (CIMP), which was known to correlate with microsatellite instability (MSI)-high CRC. To select new methylation markers genome-widely and epigenotype CRC by DNA methylation comprehensively, we performed methylated DNA immunoprecipitation-on-chip analysis using MSI-high CRC cell line HCT116 and microsatellite-stable SW480, and re-expression array analysis by 5-aza-2-deoxycytidine/Trichostatin A. Methylation levels of 44 new markers selected and 16 previously reported markers were analyzed quantitatively in 149 clinical CRC samples using MALDI-TOF mass spectrometry. By unsupervised two-way hierarchical clustering, CRC was clustered into high-, intermediate-, and low-methylation epigenotypes. Methylation markers were clustered into two groups: Group-1 showing methylation in high-methylation epigenotype and including all the 11 CIMP-related markers except NEUROG1, and Group-2 showing methylation in high- and intermediate-methylation epigenotypes. Marker panel deciding methylation epigenotypes with the highest accuracy was developed: 1st-Panel consisting of Group-1 genes (CACNA1G, LOX, SLC30A10) to extract high-methylation epigenotype, and 2nd-Panel consisting of Group-2 genes (ELMO1, FBN2, THBD, HAND1) and SLC30A10 again to divide the remains into intermediate- and low-methylation epigenotypes. High-methylation epigenotype correlated significantly with BRAF mutation, MSI, proximal tumor location, and mucinous component, in concordance with reported CIMP. Intermediate- and low-methylation epigenotypes significantly correlated with KRAS-mutation(+) and KRAS-mutation(-), respectively. KRAS-mutation(+) intermediate-methylation epigenotype showed worse prognosis than KRAS-mutation(-) low-methylation epigenotype (p=0.030). These three epigenotypes with different genetic characteristics suggested different molecular CRC genesis, and the markers might be useful to predict prognosis.

Dataset Information

Analysis of predictive biomarker and analysis of correlations between toxicities and SNPs that can be related to pharmacokinetics, in trifluridine/tipiracil hydrochloride therapy for previously fluoropyrimidine-treated elderly patients with unresectable or recurrent colorectal cancer

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