A comprehensive algorithmic dissection yields biomarker discovery and insights into the discrete stage-wise progression of colorectal cancer

Abstract

ABSTRACTColorectal cancer remains an increasingly common condition 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 contributes to the success of cancer therapy and increases the likelihood of a favorable 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 as well as contrast models 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 31 genes that are progression-significant such as ESM1, DKK1, SPDYC, IGFBP1, BIRC7, NKD1, CXCL13, VGLL1, PLAC1, SPERT, UPK2, and interestingly three members of the LY6G6 family. Significant monotonic linear model genes included HIGD1A, ACADS, PEX26, and SPIB. The existing literature for many of these biomarkers is discussed to document positive translational potential needing clinical evidence. 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.