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Identification of the predictive genes for the response of colorectal cancer patients to FOLFOX therapy.

ABSTRACT: Background:Colorectal cancer is a malignant tumor with high death rate. Chemotherapy, radiotherapy and surgery are the three common treatments of colorectal cancer. For early colorectal cancer patients, postoperative adjuvant chemotherapy can reduce the risk of recurrence. For advanced colorectal cancer patients, palliative chemotherapy can significantly improve the life quality of patients and prolong survival. FOLFOX is one of the mainstream chemotherapies in colorectal cancer, however, its response rate is only about 50%. Methods:To systematically investigate why some of the colorectal cancer patients have response to FOLFOX therapy while others do not, we searched all publicly available database and combined three gene expression datasets of colorectal cancer patients with FOLFOX therapy. With advanced minimal redundancy maximal relevance and incremental feature selection method, we identified the biomarker genes. Results:A Support Vector Machine-based classifier was constructed to predict the response of colorectal cancer patients to FOLFOX therapy. Its accuracy, sensitivity and specificity were 0.854, 0.845 and 0.863, respectively. Conclusion:The biological analysis of representative biomarker genes suggested that apoptosis and inflammation signaling pathways were essential for the response of colorectal cancer patients to FOLFOX chemotherapy.

SUBMITTER: Lin H

PROVIDER: S-EPMC6149834 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of the predictive genes for the response of colorectal cancer patients to FOLFOX therapy.

Lin Hengjun H Qiu Xueke X Zhang Bo B Zhang Jichao J

OncoTargets and therapy 20180917

<h4>Background</h4>Colorectal cancer is a malignant tumor with high death rate. Chemotherapy, radiotherapy and surgery are the three common treatments of colorectal cancer. For early colorectal cancer patients, postoperative adjuvant chemotherapy can reduce the risk of recurrence. For advanced colorectal cancer patients, palliative chemotherapy can significantly improve the life quality of patients and prolong survival. FOLFOX is one of the mainstream chemotherapies in colorectal cancer, however ...[more]

PMID: 30271178

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Project description:What is already known about this subject* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.What this study adds* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.AimsTo test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.MethodsAdvanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).ResultsNone of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).ConclusionsThese results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

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.

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Identification of the predictive genes for the response of colorectal cancer patients to FOLFOX therapy.

Publications

Identification of the predictive genes for the response of colorectal cancer patients to FOLFOX therapy.

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