Computational Identification of Novel Stage-Specific Biomarkers in Colorectal Cancer Progression

PLoS One. 2016 May 31;11(5):e0156665. doi: 10.1371/journal.pone.0156665. eCollection 2016.

Abstract

It is well-known that the conversion of normal colon epithelium to adenoma and then to carcinoma stems from acquired molecular changes in the genome. The genetic basis of colorectal cancer has been elucidated to a certain extent, and much remains to be known about the identity of specific cancer genes that are associated with the advancement of colorectal cancer from one stage to the next. Here in this study we attempted to identify novel cancer genes that could underlie the stage-specific progression and metastasis of colorectal cancer. We conducted a stage-based meta-analysis of the voluminous tumor genome-sequencing data and mined using multiple approaches for novel genes driving the progression to stage-II, stage-III and stage-IV colorectal cancer. The consensus of these driver genes seeded the construction of stage-specific networks, which were then analyzed for the centrality of genes, clustering of subnetworks, and enrichment of gene-ontology processes. Our study identified three novel driver genes as hubs for stage-II progression: DYNC1H1, GRIN2A, GRM1. Four novel driver genes were identified as hubs for stage-III progression: IGF1R, CPS1, SPTA1, DSP. Three novel driver genes were identified as hubs for stage-IV progression: GSK3B, GGT1, EIF2B5. We also identified several non-driver genes that appeared to underscore the progression of colorectal cancer. Our study yielded potential diagnostic biomarkers for colorectal cancer as well as novel stage-specific drug targets for rational intervention. Our methodology is extendable to the analysis of other types of cancer to fill the gaps in our knowledge.

Publication types

  • Meta-Analysis

MeSH terms

  • Adenoma / genetics
  • Adenoma / pathology
  • Biomarkers, Tumor / genetics
  • Carcinogenesis / genetics*
  • Colonic Neoplasms / diagnosis
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology*
  • Disease Progression*
  • Gene Expression Regulation, Neoplastic
  • Gene Ontology
  • Humans
  • Intestinal Mucosa / pathology
  • Neoplasm Metastasis / genetics*
  • Neoplasm Staging
  • Oligonucleotide Array Sequence Analysis

Substances

  • Biomarkers, Tumor

Grants and funding

The authors received no specific funding for this work.