Understanding the Impact of Non-coding Mutations in Colorectal Cancer

Abstract

The studies characterizing the genomic landscape of cancers have been majorly focused on the identification of driver mutations within the protein-coding gene regions. However, the non- coding region occupies a significantly larger proportion of the genome, and functional mutations have been reported in the regulatory regions (of non-coding regions) which can affect signaling pathways implicated in cancer. Cis-regulatory elements (CREs) are an enriched subset of the non-coding DNA and can regulate the gene expression of neighboring genes. CREs can be highly tissue-specific and hence, it becomes important to study tissue type- specific gene regulation. In this study, we used capture Hi-C data for 19,023 promoter fragments in the Colorectal cancer cell line (HT-29) from Orlando et al. and integrated it with the whole genome somatic mutation and gene expression data from PCAWG. We used the SMuRF tool to identify significantly mutated (qvalue<0.05) CREs. We identified five genes, ALCAM, PRKCH, TSC22D1, NFIB and FGFR2 with significant differential expression (p- value<0.05 and absolute fold change >= 1) in the mutated group (samples having mutations in the CRE interacting with the gene) versus the non-mutated group. Out of these five genes, we focused our analysis on FGFR2 which is a well-known cancer-driver gene, but the impact of non-coding mutations on this gene in colorectal cancer has not been reported before. We identified multiple TFBS and histone modifications in the FGFR2 CRE. We thus report a non- coding CRE interacting with the FGFR2 gene as a potential non-coding cancer driver in colorectal cancer.