Dataset Information

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

ABSTRACT: Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to fluoropyrimidine chemotherapy in patients with metastatic colorectal cancer (mCRC). We analyzed the levels of 22 miRNAs and the Dicer protein in primary tumors from patients with mCRC who were treated with first-line capecitabine monotherapy within the CAIRO trial of the Dutch Colorectal Cancer Group. Correlation between the expression status of miRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. Patients with low expression of miR-143 in their primary tumor had increased median PFS compared to those with high expression of miR-143. Furthermore, FXYD3, an ion transport regulator and a putative target of miR-143, also showed an association with PFS. These findings warrant further studies to investigate the relationship between miR-143, FXYD3 and fluoropyrimidines, and the clinical utility of miR-143 as biomarker.

SUBMITTER: Simmer F

PROVIDER: S-EPMC4673216 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

Simmer Femke F Venderbosch Sabine S Dijkstra Jeroen R JR Vink-Börger Elisa M EM Faber Claudius C Mekenkamp Leonie J LJ Koopman Miriam M De Haan Anton F AF Punt Cornelis J CJ Nagtegaal Iris D ID

Oncotarget 20150901 26

Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to flu ...[more]

PMID: 26392389

Similar Datasets

Project description:BackgroundThe randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC.Materials and methodsDNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG).ResultsPatient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS).ConclusionChromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC.Implications for practiceBevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

Project description:Resistance to 5-Fluorouracil (5-FU) is a major obstacle to the successful treatment of colorectal cancer (CRC) and posed an increased risk of recurrence. DNA methylation has been suggested as one of the underlying mechanisms for recurrent disease and its contribution to the development of drug resistance remains to be clarified. This study aimed to determine the methylation phenotype in CRC for identification of predictive markers for chemotherapy response. We performed DNA methylation profiling on 43 non-recurrent and five recurrent CRC patients using the Illumina Infinium HumanMethylation450 Beadchip assay. In addition, CRC cells with different genetic backgrounds, response to 5-FU and global methylation levels (HT29 and SW48) were treated with 5-FU and DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC). The singular and combined effects of these two drug classes on cell viability and global methylation profiles were investigated. Our genome-wide methylation study on the clinical specimens showed that recurrent CRCs exhibited higher methylation levels compared to non-recurrent CRCs. We identified 4787 significantly differentially methylated genes (P < 0.05); 3112 genes were hyper- while 1675 genes were hypomethylated in the recurrent group compared to the non-recurrent. Fifty eight and 47 of the significantly hypermethylated and hypomethylated genes have an absolute recurrent/non-recurrent methylation difference of ?20%. Most of the hypermethylated genes were involved in the MAPK signaling pathway which is a key regulator for apoptosis while the hypomethylated genes were involved in the PI3K-AKT signaling pathway and proliferation process. We also demonstrate that 5-azadC treatment enhanced response to 5-FU which resulted in significant growth inhibition compared to 5-FU alone in hypermethylated cell lines SW48. In conclusion, we found the evidence of five potentially biologically important genes in recurrent CRCs that could possibly serve as a new potential therapeutic targets for patients with chemoresistance. We postulate that aberrant methylation of CCNEI, CCNDBP1, PON3, DDX43, and CHL1 in CRC might be associated with the recurrence of CRC and 5-azadC-mediated restoration of 5-FU sensitivity is mediated at least in part by MAPK signaling pathway.

Dataset Information

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

Publications

MicroRNA-143 is a putative predictive factor for the response to fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets