COADREADx: A comprehensive algorithmic dissection unravels salient biomarkers and actionable insights into the discrete progression of colorectal cancer

Abstract

Colorectal cancer remains an increasingly common disease with uncommon burden of disease, heterogeneity in manifestation, and no definitive treatment. Against this backdrop, renewed efforts to unravel the genetic drivers of colorectal cancer progression are paramount. Early-stage detection of cancer increases success of treatment as well as prognosis. Here, we have executed a comprehensive computational workflow aimed at uncovering the discrete stagewise genetic drivers of colorectal cancer progression. Using the TCGA COADREAD expression data and clinical metadata, we constructed stage-specific linear models and contrasts to identify stage-specific differentially expressed genes. Stage-specific differentially expressed genes with a significant monotone trend of expression across the stages were identified as progression-significant biomarkers. Among the biomarkers identified are: CRLF1, CALB2 (stage-I specific), GREM2, ADCY5, PLAC2, DMRT3 (stage-II specific), PIGR, SLC26A9 (stage-III specific), GABRD, DLX3, CST6, HOTAIR (stage-IV specific), and CDH3, KRT80, AADACL2, OTOP2, FAM135B, HSP90AB1 (top linear model genes). In particular the study yielded 19 genes that are progression-significant such as CCDC19, SERPINE1, HOXC11, SOX10. The existing literature for many of these biomarkers are discussed and analyzed for encouraging evidence of translational utility that would still need clinical validation. The study yielded many classes of biomarkers, which could serve in signature panels for early-stage colorectal cancer diagnosis as well as establish strategies for therapy. Our work is a concrete step in the direction of establishing the molecular signatures of the discrete progressive stages of colorectal cancer, with the future goal of securing more effective treatment for the condition.

Low Expression of AGPAT5 Is Associated With Clinical Stage and Poor Prognosis in Colorectal Cancer and Contributes to Tumour Progression

“…32 Sangeetha Muthamilselvan et al 33 found that FBN1 as a stage I-salient hyper methylated gene, FOXG1 as a stage II-salient hyper methylated gene, HCN1 as stage III-salient hyper methylated gene, and NELL1, ZNF135, FAM123A, LAMA1 as stage IV-salient hyper methylated genes, which would drive the progression of CRC. Ashok Palaniappan and Sarathi 34 reported that CRLF1, CALB2 as stage I-specific differentially expressed genes (DEGs), GREM2, ADCY5, PLAC2, and DMRT3 as stage II-specific DEGs, PIGR and SLC26A9 as stage III-specific DEGs, and GABRD, DLX3, CST6, and HOTAIR as stage IV-specific DEGs, which were identified as progression-significant biomarkers. However, overall trend changes in gene expression in stages I to IV of CRC have not been reported.…”

Inflammatory Bowel Disease in patients with Primary Sclerosing Cholangitis: a distinct form of colitis

“…Therefore, we compared the expression of known cancer related genes (i.e. tumour suppressor and oncogenes) in stem cells between UC and PSC-IBD, in both inflamed and non-inflamed states [29]. For both the non-inflamed state and the inflamed state, we found that similar ratios of tumour suppressor to oncogenes were upregulated in stem cells in PSC-IBD and UC.…”