IDDF2018-ABS-0241 Epigenetics of mucinous colorectal adenocarcinoma through integrated transcriptome, methylome and mirnome analysis

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Abstract

Background

Mucinous cancer (MC) is a distinctive subtype of colorectal cancer (CRC) identified in 10%–15% of patients. It has long been associated with poor response to treatment, low survival rates, worse prognosis and present at more advanced stage than non-mucinous adenocarcinoma. Yet, the knowledge on the molecular mechanisms associated with this type of malignancy is lacking. This study aims to elucidate the transcriptome, methylome and miRnome landscape of MC for a better understanding of the disease and to find the potential target of therapy.

Methods

We obtained the TCGA-generated methylation data based on Illumina Methylation 450 beadchip, level 3 microRNA expression and RNA sequencing dataset from Firebrowse. Gene expression data from 41 normal colons and methylation data from 45 normal colons were included for comparisons. Unpaired t-test with multiple testing corrections was performed using Bioconductor in R version 3.4.3.

Results

Despite originating from the similar organ, MC and AC have distinct molecular profiles as shown by a high number of differentially methylated and expressed genes. We identified 2420 significant demethylated genes, and 3899 differentially expressed genes in MC. LY6G6D is the most downregulated gene while MUC2, the commonly discussed gene in MC, is the most upregulated. There were only four significant differentially expressed microRNAs with modest fold change, suggesting that DNA methylation is a more dominant epigenetic event in gene regulation of MC. EIF6 is the most significantly hypermethylated (25.6% hypermethylation; p=4.18E-10) in MC versus AC and its expression was downregulated −0.57 fold (p=4.89E-07). On the other hand, BAG3 is the most significantly hypomethylated (22.1% hypomethylation, p=0.009) despite modest but significant upregulation of expression (0.24, p=8.20E-03).

Conclusions

Our findings could be the first to suggest that the up- and downregulation of BAG3 and EIF6 expression in MC could be due to hypo- and hypermethylation, however, their specific roles in MC tumourigenesis remains to be elucidated. Beyond mucin genes, upregulation of genes rarely associated with CRC was also observed, suggesting new insight into the aetiology of MC resistance to therapies and their roles as a potential target for MC treatment may be worth investigating.

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