Toward Colorectal Cancer Biomarkers: The Role of Genetic Variation, Wnt Pathway, and Long Noncoding RNAs

Colorectal cancer (CRC) is the third leading cause of death worldwide, comprising nearly 8% of cancer-related deaths per year. In South Korea, for example, CRC is the second most common cancer in men, and third in women. This study reports on the association of CRC with genetic variations in long noncoding RNAs, activators, and inhibitors of a cell proliferation pathway. Five normal colon mucosa tissue samples and their matched five-stage IV CRC samples were evaluated (dataset Gene Expression Omnibus accession: GSE50760). We identified more than 5000 differentially expressed genes (DEGs). The Wnt pathway had the greatest portion of DEGs, including activators, inhibitors, and associated long noncoding RNAs (lncRNAs), suggesting the importance of Wnt pathway in CRC. The following genes were aberrantly expressed: WIF1, SFRP4, CD82, WNT2, WNT3, WNT5A, HOTAIR, CRNDE, and UCA1. Notably, HOTAIR is known to silence WIF1, and WIF1 inhibits the Wnt ligands to negatively regulate the pathway. The lncRNA CRNDE positively regulates WNT5A, while UCA1 positively regulates WNT2 and WNT3. We note that HOTAIR was unable to silence WIF1. CRNDE and UCA1 were found to be upregulated, which may explain the high expression of the WIF1 targets. Furthermore, 10 single-nucleotide polymorphisms (SNPs) were identified in five of the candidate genes above. A possible novel SNP in CD82, chr11:44619242T > C, was predicted to introduce a ZBTB7A binding site. These SNPs are hypothesized to contribute to aberrant and discrepant regulation of the Wnt pathway in a context of CRC pathogenesis. These findings collectively inform future research on diagnostics and therapeutics innovation in CRC.