Game-theoretic link relevance indexing on genome-wide expression dataset identifies putative salient genes with potential etiological and diapeutics role in colorectal cancer

Abstract

Diapeutics gene markers in colorectal cancer (CRC) can help manage mortality caused by the disease. We applied a game-theoretic link relevance Index (LRI) scoring on the high-throughput whole-genome transcriptome dataset to identify salient genes in CRC and obtained 126 salient genes with LRI score greater than zero. The biomarkers database lacks preliminary information on the salient genes as biomarkers for all the available cancer cell types. The salient genes revealed eleven, one and six overrepresentations for major Biological Processes, Molecular Function, and Cellular components. However, no enrichment with respect to chromosome location was found for the salient genes. Significantly high enrichments were observed for several KEGG, Reactome and PPI terms. The survival analysis of top protein-coding salient genes exhibited superior prognostic characteristics for CRC. MIR143HG, AMOTL1, ACTG2 and other salient genes lack sufficient information regarding their etiological role in CRC. Further investigation in LRI methodology and salient genes to augment the existing knowledge base may create new milestones in CRC diapeutics.

Figure 1

Distribution of LRI values of the salient genes. The figure exhibits the distribution of 126 salient genes. Violin plot (A) with jittered points data points and mean value, Q–Q plot (B) and histogram combined density plot (C) to show distribution LRI values of these 126 salient genes. (D) Comparison of the 124 salient genes (out of 126 Gene IDs, two Gene IDs did not map to Entrez ID) with 171 (after removing duplicates from the total 180 genes) unique cancer biomarkers from CellMarker database exhibits overlap of only two genes and 122 genes exhibits uniqueness. (E) Comparison of the 124 salient genes with 24 DEGs of CRC exhibits overlap of only two genes.

Figure 2

Enrichment of the major Biological Processes (BP) associated with the 126 salient genes. (A) Represents the network of various sub-ontologies, and associated genes, (B) describes percentage terms per group for various BP that are significantly enriched in pie chart and (C) number of genes in each term with significance sign. Node size is inversely proportioned to the p-value, i.e., the lower the value, the bigger the node size and color represent a different group of terms. *Significant at p ≤ 0.05, and **Significant at p ≤ 0.001.

Figure 3

Enrichment of the major Molecular Function (MF) (A) and Cellular component (CC) associated with the 126 salient genes. (A) Describes percentage terms per group for various MF that are significantly enriched, and (B) shows various sub-ontologies of CC and associated genes. Node size is inversely proportional to the p-value, i.e., the smaller the value more considerable the node size and colour represents a different group of terms.

Figure 4

Enrichment of the major KEGG pathways associated with the 126 LRI genes. (A) Represents the network of various pathways and sub-pathways and associated genes where the size of the node is inversely proportional to the p-value, i.e., the lower the p-value, the bigger the node size and colour represents a different group of pathway terms. (B) Describes percentage terms per group for various parent pathways significantly enriched in pie chart, and (C) describes the number of genes in each pathway and sub-pathway term with significance sign. *Significant at p ≤ 0.05, and **Significant at p ≤ 0.001.

Figure 5

Enrichment of the major Reactome pathways and reactions. The figure represents the Enrichment of the Reactome pathways (A) and reactions (B) associated with the 126 salient genes (Labeled in red colour). Node size is inversely proportional to the p-value, i.e., the lower the p-value, the bigger the node size and colour represents a different group of terms.

Figure 6

Protein–Protein interaction (PPI) network among the 126 salient genes. At a confidence score of 0.700, the figure exhibits major interactions among the protein-coding genes as node and various interactions as edges. The colored nodes are query proteins with 3D structures (if any) inside the node and edge color represents evidence as an indicator of interactions among the proteins. The isolated nodes were removed from the network.

Figure 7

Diapeutics implication of top 10 protein-coding salient genes in CRC. Kaplan–Meier (KM) survival analysis of overall survival with respect to expression of top 10 protein-coding salient genes in CRC samples. In each plot, the abscissa represents ‘Time in Years’ and the ordinate represent ‘Survival Probability’. Log-rank p-value for KM plot represents a significant correlation between mRNA expression level and patient survival by exhibiting significant differences in survival between genes’ high and low expression. Protein-coding salient genes exhibited statistically significant (log-rank p-value ≤ 0.05) in the overall survival endpoint (refer to Supplementary File Figure S1–S10 for enlarged view).