Methylation Profile of Cancer Testis Antigens in Colorectal Cancer.

Background: Cancer testis antigens (CTAs) are a class of immune-stimulating antigens often overexpressed in many types of cancers. The usage of the CTAs as immunotherapy targets have been widely investigated in different cancers including melanoma, hematological malignancies, and colorectal cancer. Studies have indicated that the epigenetic regulation of the CTAs such as the methylation status may affect the expression of the CTAs. However, the report on the methylation status of the CTAs is conflicting. The general methylation profile of the CTAs, especially in colorectal cancer, is still elusive. Objective: To determine the methylation profile of the selected CTAs in our colorectal cancer patients. Methods: A total of 54 pairs of colorectal cancer samples were subjected to DNA methylation profiling using the Infinium Human Methylation 450K bead chip. Results: We found that most of the CTAs were hypomethylated, and CCNA1 and TMEM108 genes were among the few CTAs that were hypermethylated. Conclusion: Overall, our brief report has managed to show the overall methylation profile in over the 200 CTAs in colorectal cancer and this could be used for further refining any immunotherapy targets.

Hypercholesterolemia in the Malaysian Cohort Participants: Genetic and Non-Genetic Risk Factors.

Hypercholesterolemia was prevalent in 44.9% of The Malaysian Cohort participants, of which 51% were Malay. This study aimed to identify the variants involved in hypercholesterolemia among Malays and to determine the association between genetic and non-genetic risk factors. This nested case-control study included 25 Malay participants with the highest low-density lipoprotein cholesterol (LDL-C, >4.9 mmol/L) and total cholesterol (TC, >7.5 mmol/L) and 25 participants with the lowest LDL-C/TC. Genomic DNA was extracted, and whole-exome sequencing was performed using the Ion ProtonTM system. All variants were annotated, filtered, and cross-referenced against publicly available databases. Forty-five selected variants were genotyped in 677 TMC Malay participants using the MassARRAY® System. The association between genetic and non-genetic risk factors was determined using logistic regression analysis. Age, fasting blood glucose, tobacco use, and family history of hyperlipidemia were significantly associated with hypercholesterolemia. Participants with the novel OSBPL7 (oxysterol-binding protein-like 7) c.651_652del variant had 17 times higher odds for hypercholesterolemia. Type 2 diabetes patients on medication and those with PCSK9 (proprotein convertase subtilisin/kexin type 9) rs151193009 had low odds for hypercholesterolemia. Genetic predisposition can interact with non-genetic factors to increase hypercholesterolemia risk in Malaysian Malays.

Association between CYP2E1 polymorphisms and colorectal cancer risk: a systematic review and meta-analysis.

CYP2E1 encodes an enzyme that participates in the activation of several carcinogenic substances. Thus, numerous studies have investigated the association between CYP2E1 polymorphisms and colorectal cancer (CRC) risk, but inconclusive results have been obtained. We performed a meta-analysis to precisely evaluate the relationship of CYP2E1 rs2031920, rs3813867, and rs6413432 polymorphisms with the susceptibility to CRC. Scopus, Web of Science and PubMed databases were searched to identify eligible studies, and the association between the polymorphisms and CRC risk was then quantitatively synthesized using different genetic models. Eighteen studies with 23,598 subjects were selected for inclusion into the analysis. Significant association between rs2031920 and an increased CRC risk was observed in homozygous (OR = 1.496, 95% CI 1.177-1.901, P = 0.001), recessive (OR = 1.467, 95% CI 1.160-1.857, P = 0.001) and allele (OR = 1.162, 95% CI 1.001-1.349, P = 0.048) models. Significant association was not found for rs3813867 and rs6413432 (P > 0.05). In conclusion, our results suggest that rs2031920, but not rs3813867 and rs6413432, is associated with the risk of CRC.

Genetic Factors for Coronary Heart Disease and Their Mechanisms: A Meta-Analysis and Comprehensive Review of Common Variants from Genome-Wide Association Studies.

Genome-wide association studies (GWAS) have discovered 163 loci related to coronary heart disease (CHD). Most GWAS have emphasized pathways related to single-nucleotide polymorphisms (SNPs) that reached genome-wide significance in their reports, while identification of CHD pathways based on the combination of all published GWAS involving various ethnicities has yet to be performed. We conducted a systematic search for articles with comprehensive GWAS data in the GWAS Catalog and PubMed, followed by a meta-analysis of the top recurring SNPs from ≥2 different articles using random or fixed-effect models according to Cochran Q and I2 statistics, and pathway enrichment analysis. Meta-analyses showed significance for 265 of 309 recurring SNPs. Enrichment analysis returned 107 significant pathways, including lipoprotein and lipid metabolisms (rs7412, rs6511720, rs11591147, rs1412444, rs11172113, rs11057830, rs4299376), atherogenesis (rs7500448, rs6504218, rs3918226, rs7623687), shared cardiovascular pathways (rs72689147, rs1800449, rs7568458), diabetes-related pathways (rs200787930, rs12146487, rs6129767), hepatitis C virus infection/hepatocellular carcinoma (rs73045269/rs8108632, rs56062135, rs188378669, rs4845625, rs11838776), and miR-29b-3p pathways (rs116843064, rs11617955, rs146092501, rs11838776, rs73045269/rs8108632). In this meta-analysis, the identification of various genetic factors and their associated pathways associated with CHD denotes the complexity of the disease. This provides an opportunity for the future development of novel CHD genetic risk scores relevant to personalized and precision medicine.

TCGA-My: A Systematic Repository for Systems Biology of Malaysian Colorectal Cancer.

Colorectal cancer (CRC) ranks second among the most commonly occurring cancers in Malaysia, and unfortunately, its pathobiology remains unknown. CRC pathobiology can be understood in detail with the implementation of omics technology that is able to generate vast amounts of molecular data. The generation of omics data has introduced a new challenge for data organization. Therefore, a knowledge-based repository, namely TCGA-My, was developed to systematically store and organize CRC omics data for Malaysian patients. TCGA-My stores the genome and metabolome of Malaysian CRC patients. The genome and metabolome datasets were organized using a Python module, pandas. The variants and metabolites were first annotated with their biological information using gene ontologies (GOs) vocabulary. The TCGA-My relational database was then built using HeidiSQL PorTable 9.4.0.512, and Laravel was used to design the web interface. Currently, TCGA-My stores 1,517,841 variants, 23,695 genes, and 167,451 metabolites from the samples of 50 CRC patients. Data entries can be accessed via search and browse menus. TCGA-My aims to offer effective and systematic omics data management, allowing it to become the main resource for Malaysian CRC research, particularly in the context of biomarker identification for precision medicine.

Inhibitory Mechanism of Combined Hydroxychavicol With Epigallocatechin-3-Gallate Against Glioma Cancer Cell Lines: A Transcriptomic Analysis.

Emerging reports have shown therapeutic potential of hydroxychavicol (HC) and epigallocatechin-3-gallate (EGCG) against cancer cells, however high concentrations are required to achieve the anticancer activity. We reported the synergy of low combination doses of EGCG+HC in glioma cell lines 1321N1, SW1783, and LN18 by assessing the effects of EGCG+HC through functional assays. Using high throughput RNA sequencing, the molecular mechanisms of EGCG+HC against glioma cell lines were revealed. EGCG/HC alone inhibited the proliferation of glioma cell lines, with IC50 values ranging from 82 to 302 µg/ml and 75 to 119 µg/ml, respectively. Sub-effective concentrations of combined EGCG+HC enhanced the suppression of glioma cell growth, with SW1783 showing strong synergism with a combination index (CI) of 0.55 and LN18 showing a CI of 0.51. A moderate synergistic interaction of EGCG+HC was detected in 1321N1 cells, with a CI value of 0.88. Exposure of 1321N1, SW1783, and LN18 cells to EGCG+HC for 24 h induces cell death, with caspase-3 activation rates of 52%, 57%, and 9.4%, respectively. However, the dose for SW1783 is cytotoxic to normal cells, thus this dose was excluded from other tests. EGCG+HC induced cell cycle arrest at S phase and reduced 1321N1 and LN18 cell migration and invasion. Combined EGCG+HC amplified its anticancer effect by downregulating the axon guidance process and metabolic pathways, while simultaneously interfering with endoplasmic reticulum unfolded protein response pathway. Furthermore, EGCG+HC exerted its apoptotic effect through the alteration of mitochondrial genes such as MT-CO3 and MT-RNR2 in 1321N1 and LN18 cells respectively. EGCG+HC dynamically altered DYNLL1 alternative splicing expression in 1321N1 and DLD splicing expression in LN18 cell lines. Our work indicated the pleiotropic effects of EGCG+HC treatment, as well as particular target genes that might be investigated for future glioma cancer therapeutic development.

Investigating Genetic and Other Determinants of First-Onset Myocardial Infarction in Malaysia: Protocol for the Malaysian Acute Vascular Events Risk Study.

BACKGROUND: Although the burden of premature myocardial infarction (MI) is high in Malaysia, direct evidence on the determinants of MI in this multi-ethnic population remains sparse. OBJECTIVE: The Malaysian Acute Vascular Events Risk (MAVERIK) study is a retrospective case-control study established to investigate the genomic, lipid-related, and other determinants of acute MI in Malaysia. In this paper, we report the study protocol and early results. METHODS: By June 2019, we had enrolled approximately 2500 patients with their first MI and 2500 controls without cardiovascular disease, who were frequency-matched by age, sex, and ethnicity, from 17 hospitals in Malaysia. For each participant, serum and whole blood have been collected and stored. Clinical, demographic, and behavioral information has been obtained using a 200-item questionnaire. RESULTS: Tobacco consumption, a history of diabetes, hypertension, markers of visceral adiposity, indicators of lower socioeconomic status, and a family history of coronary disease were more prevalent in cases than in controls. Adjusted (age and sex) logistic regression models for traditional risk factors indicated that current smoking (odds ratio [OR] 4.11, 95% CI 3.56-4.75; P<.001), previous smoking (OR 1.34, 95% CI 1.12-1.60; P=.001), a history of high blood pressure (OR 2.13, 95% CI 1.86-2.44; P<.001), a history of diabetes mellitus (OR 2.72, 95% CI 2.34-3.17; P<.001), a family history of coronary heart disease (OR 1.28, 95% CI 1.07-1.55; P=.009), and obesity (BMI >30 kg/m2; OR 1.19, 95% CI 1.05-1.34; P=.009) were associated with MI in age- and sex-adjusted models. CONCLUSIONS: The MAVERIK study can serve as a useful platform to investigate genetic and other risk factors for MI in an understudied Southeast Asian population. It should help to hasten the discovery of disease-causing pathways and inform regionally appropriate strategies that optimize public health action. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/31885.

Coronary Heart Disease in Type 2 Diabetes Mellitus: Genetic Factors and Their Mechanisms, Gene-Gene, and Gene-Environment Interactions in the Asian Populations.

Asians are more susceptible to type 2 diabetes mellitus (T2D) and its coronary heart disease (CHD) complications than the Western populations, possibly due to genetic factors, higher degrees of obesity, insulin resistance, and endothelial dysfunction that could occur even in healthy individuals. The genetic factors and their mechanisms, along with gene-gene and gene-environment interactions associated with CHD in T2D Asians, are yet to be explored. Therefore, the objectives of this paper were to review the current evidence of genetic factors for CHD, summarize the proposed mechanisms of these genes and how they may associate with CHD risk, and review the gene-gene and gene-environment interactions in T2D Asians with CHD. The genetic factors can be grouped according to their involvement in the energy and lipoprotein metabolism, vascular and endothelial pathology, antioxidation, cell cycle regulation, DNA damage repair, hormonal regulation of glucose metabolism, as well as cytoskeletal function and intracellular transport. Meanwhile, interactions between single nucleotide polymorphisms (SNPs) from different genes, SNPs within a single gene, and genetic interaction with environmental factors including obesity, smoking habit, and hyperlipidemia could modify the gene's effect on the disease risk. Collectively, these factors illustrate the complexities of CHD in T2D, specifically among Asians.

Somatic mitochondrial DNA mutations in different grades of glioma.

Aim: Mitochondrial DNA (mtDNA) alterations play an important role in the multistep processes of cancer development. Gliomas are among the most diagnosed brain cancer. The relationship between mtDNA alterations and different grades of gliomas are still elusive. This study aimed to elucidate the profile of somatic mtDNA mutations in different grades of gliomas and correlate it with clinical phenotype. Materials & methods: Forty histopathologically confirmed glioma tissue samples and their matched blood were collected and subjected for mtDNA sequencing. Results & conclusion: About 75% of the gliomas harbored at least one somatic mutation in the mtDNA gene, and 45% of these mutations were pathogenic. Mutations were scattered across the mtDNA genome, and the commonest nonsynonymous mutations were located at complex I and IV of the mitochondrial respiratory chain. These findings may have implication for future research to determine the mitochondrial energetics and its downstream metabolomics on gliomas.

Cancer testis antigen PASD1 expression and immunogenicity in human colorectal cancer and polyps.

Colorectal cancer (CRC) is a malignant tumor arising from a human inner colon lining that may spread to other organs such as the liver and lungs. Per ARNT Sim domain containing 1 (PASD1) is a cancer-testis antigen expressed in cancers including CRC but not in normal tissues except for normal testes. This study aims to study PASD1 protein as a potential target for CRC immunotherapy. A total of 90 CRC and polyps tissue samples were investigated for PASD1 RNA and protein expression using a real-time polymerase chain reaction and immunohistochemical staining, respectively. Matched patients' peripheral blood mononuclear cells were pulsed with PASD1 peptides and measured for immunogenicity, cell cytotoxicity, and cytokine assays. The clinical data were collected and analyzed accordingly. Our results show that PASD1_v2 mRNA expression was highly expressed in CRC (46.0%) and polyps samples (33.3%). Both PASD1-1 and PASD1-2 proteins were expressed in 31.7% of CRC and 29.4% of polyps samples. Protein expression was weak to moderate positive in the cytoplasm and/or nucleus of the tissues. Immune responses towards CD4-specific PASD1 peptides were detected in 21.7% of CRC and 23.5% of polyps patients. The most immunogenic peptide was PASD1 (1) in CRC while PASD1 (3) in polyps. Cytotoxicity effects were detected up to 57.20% observed in CRC samples while IL-17A and IL-6 cytokines were highly expressed. The demographic data suggest that Chinese female patients more than 60 years old, diagnosed with late-stage rectosigmoid tumors may benefit from the PASD1 peptide immunotherapy approach. This is the first report describing CD4-positive T-helper response to the PASD1 positive CRC patients and its cytotoxicity.

Whole genome sequencing of Malaysian colorectal cancer patients reveals specific druggable somatic mutations.

The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/ß-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.

Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer.

Dysbiosis of the gut microbiome has been associated with the pathogenesis of colorectal cancer (CRC). We profiled the microbiome of gut mucosal tissues from 18 CRC patients and 18 non-CRC controls of the UKM Medical Centre (UKMMC), Kuala Lumpur, Malaysia. The results were then validated using a species-specific quantitative PCR in 40 CRC and 20 non-CRC tissues samples from the UMBI-UKMMC Biobank. Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were found to be over-represented in our CRC patients compared to non-CRC controls. These four bacteria markers distinguished CRC from controls (AUROC = 0.925) in our validation cohort. We identified bacteria species significantly associated (cut-off value of > 5 fold abundance) with various CRC demographics such as ethnicity, gender and CRC staging; however, due to small sample size of the discovery cohort, these results could not be further verified in our validation cohort. In summary, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were enriched in our local CRC patients. Nevertheless, the roles of these bacteria in CRC initiation and progression remains to be investigated.

Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells.

Despite the advancements in primary brain tumour diagnoses and treatments, the mortality rate remains high, particularly in glioblastoma (GBM). Chemoresistance, predominantly in recurrent cases, results in decreased mean survival of patients with GBM. We aimed to determine the chemosensitisation and oncogenic characteristics of zinc finger protein 36-like 2 (ZFP36L2) in LN18 GBM cells via RNA interference (RNAi) delivery. We conducted a meta-analysis of microarray datasets and RNAi screening using pooled small interference RNA (siRNA) to identify the druggable genes responsive to GBM chemosensitivity. Temozolomide-resistant LN18 cells were used to evaluate the effects of gene silencing on chemosensitisation to the sub-lethal dose (1/10 of the median inhibitory concentration [IC50]) of temozolomide. ZFP36L2 protein expression was detected by western blotting. Cell viability, proliferation, cell cycle and apoptosis assays were carried out using commercial kits. A human apoptosis array kit was used to determine the apoptosis pathway underlying chemosensitisation by siRNA against ZFP36L2 (siZFP36L2). Statistical analyses were performed using one-way analysis of variance; p > 0.05 was considered significant. The meta-analysis and RNAi screening identified ZFP36L2 as a potential marker of GBM. ZFP36L2 knockdown significantly induced apoptosis (p < 0.05). Moreover, ZFP36L2 inhibition led to increased cell cycle arrest and decreased cell proliferation. Downstream analysis showed that the sub-lethal dose of temozolomide and siZFP26L2 caused major upregulation of BCL2-associated X, apoptosis regulator (BAX). ZFP36L2 has oncogenic and chemosensitive characteristics and may play an important role in gliomagenesis through cell proliferation, cell cycle arrest and apoptosis. This suggests that RNAi combined with chemotherapy treatment such as temozolomide may be a potential GBM therapeutic intervention in the future.

Extracellular Vesicles Derived From Colorectal Cancer Affects CD8 T Cells: An Analysis Based on Body Mass Index.

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. It has been shown that the body-mass index (BMI) of the patients could influence the tumor microenvironment, treatment response, and overall survival rates. Nevertheless, the mechanism on how BMI affects the tumorigenesis process, particularly the tumor microenvironment is still elusive. Herein, we postulate that extracellular vesicles (EVs) from CRC patients and non-CRC volunteers with different BMI could affect immune cells differently, in CD8 T cells particularly. We isolated the EVs from the archived serum of CRC patients with high and low BMI, as well as healthy controls with similar BMI status. The EVs were further characterized via electron microscopy, western blot and dynamic light scattering. Then, functional analysis was performed on CD8 T cells including apoptosis, cell proliferation, gene expression profiling and cytokine release upon co-incubation with the different EVs. Our results suggest that CRC-derived EVs were able to regulate the CD8 T cells. In some assays, low BMI EVs were functionally different than high BMI EVs. This study highlights the possible difference in the regulatory mechanism of cancer patients-derived EVs, especially on CD8 T cells.

Delineating colorectal cancer distribution, interaction, and risk prediction by environmental risk factors and serum trace elements.

The burden of colorectal cancer (CRC) is increasing worldwide especially in developing countries. This phenomenon may be attributable to lifestyle, dietary and environmental risk factors. We aimed to determine the level of 25 trace elements, their interaction with environmental risk factors, and subsequently develop a risk prediction model for CRC (RPM CRC). For the discovery phase, we used a hospital-based case-control study (CRC and non-CRC patients) and in the validation phase we analysed pre-symptomatic samples of CRC patients from The Malaysian Cohort Biobank. Information on the environmental risk factors were obtained and level of 25 trace elements measured using the ICP-MS method. CRC patients had lower Zn and Se levels but higher Li, Be, Al, Co, Cu, As, Cd, Rb, Ba, Hg, Tl, and Pb levels compared to non-CRC patients. The positive interaction between red meat intake ≥ 50 g/day and Co ≥ 4.77 µg/L (AP 0.97; 95% CI 0.91, 1.03) doubled the risk of CRC. A panel of 24 trace elements can predict simultaneously and accurate of high, moderate, and low risk of CRC (accuracy 100%, AUC 1.00). This study provides a new input on possible roles for various trace elements in CRC as well as using a panel of trace elements as a screening approach to CRC.

The Landscape of Tumor-Specific Antigens in Colorectal Cancer.

Over the last few decades, major efforts in cancer research and treatment have intensified. Apart from standard chemotherapy approaches, immunotherapy has gained substantial traction. Personalized immunotherapy has become an important tool for cancer therapy with the discovery of immune checkpoint inhibitors. Traditionally, tumor-associated antigens are used in immunotherapy-based treatments. Nevertheless, these antigens lack specificity and may have increased toxicity. With the advent of next-generation technologies, the identification of new tumor-specific antigens is becoming more important. In colorectal cancer, several tumor-specific antigens were identified and functionally validated. Multiple clinical trials from vaccine-based and adoptive cell therapy utilizing tumor-specific antigens have commenced. Herein, we will summarize the current landscape of tumor-specific antigens particularly in colorectal cancer.

Genome-Wide Open Chromatin Methylome Profiles in Colorectal Cancer.

The methylome of open chromatins was investigated in colorectal cancer (CRC) to explore cancer-specific methylation and potential biomarkers. Epigenome-wide methylome of open chromatins was studied in colorectal cancer tissues using the Infinium DNA MethylationEPIC assay. Differentially methylated regions were identified using the ChAMP Bioconductor. Our stringent analysis led to the discovery of 2187 significant differentially methylated open chromatins in CRCs. More hypomethylated probes were observed and the trend was similar across all chromosomes. The majority of hyper- and hypomethylated probes in open chromatin were in chromosome 1. Our unsupervised hierarchical clustering analysis showed that 40 significant differentially methylated open chromatins were able to segregate CRC from normal colonic tissues. Receiver operating characteristic analyses from the top 40 probes revealed several significant, highly discriminative, specific and sensitive probes such as OPLAH cg26256223, EYA4 cg01328892, and CCNA1 cg11513637, among others. OPLAH cg26256223 hypermethylation is associated with reduced gene expression in the CRC. This study reports many open chromatin loci with novel differential methylation statuses, some of which with the potential as candidate markers for diagnostic purposes.

Knockdown of Tousled­like kinase 1 inhibits survival of glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumour that commonly exhibits resistance to treatment. The tumour is highly heterogenous and complex kinomic alterations have been reported leading to dysregulation of signalling pathways. The present study aimed to investigate the novel kinome pathways and to identify potential therapeutic targets in GBM. Meta­analysis using Oncomine identified 113 upregulated kinases in GBM. RNAi screening was performed on identified kinases using ON­TARGETplus siRNA library on LN18 and U87MG. Tousled­like kinase 1 (TLK1), which is a serine/threonine kinase was identified as a potential hit. In vitro functional validation was performed as the role of TLK1 in GBM is unknown. TLK1 knockdown in GBM cells significantly decreased cell viability, clonogenicity, proliferation and induced apoptosis. TLK1 knockdown also chemosensitised the GBM cells to the sublethal dose of temozolomide. The downstream pathways of TLK1 were examined using microarray analysis, which identified the involvement of DNA replication, cell cycle and focal adhesion signalling pathways. In vivo validation of the subcutaneous xenografts of stably transfected sh­TLK1 U87MG cells demonstrated significantly decreased tumour growth in female BALB/c nude mice. Together, these results suggested that TLK1 may serve a role in GBM survival and may serve as a potential target for glioma.

Integrative meta-analysis for the identification of hub genes in chemoresistant colorectal cancer.

Background: Finding a new target or a new drug to overcome chemoresistance is difficult due to the heterogenous nature of cancer. Meta-analysis was performed to combine the analysis of different microarray studies to get a robust discovery. Materials & methods: Herein, we analyzed three microarray datasets on combination of folinic acid, fluorouracil, and oxaliplatin drugs (FOLFOX) resistance that fit our inclusion/exclusion criteria and performed a meta-analysis using the OmiCC system. Results: We identified several deregulated genes and we discovered HNF4A as a hub gene. We performed functional validation and observed that by targeting HNF4A, HCT116 cells were more sensitive toward both oxaliplatin and 5-fluorouracil significantly. Conclusion: Our findings show that HNF4A could be a potential target in overcoming FOLFOX chemoresistance in colorectal cancer.