Prediction and testing of biological networks underlying intestinal cancer

Vishal N. Patel, Gurkan Bebek, John M. Mariadason, Donghai Wang, Leonard H. Augenlicht, Mark R. Chance

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Colorectal cancer progresses through an accumulation of somatic mutations, some of which reside in so-called "driver" genes that provide a growth advantage to the tumor. To identify points of intersection between driver gene pathways, we implemented a network analysis framework using protein interactions to predict likely connections - both precedented and novel - between key driver genes in cancer. We applied the framework to find significant connections between two genes, Apc and Cdkn1a (p21), known to be synergistic in tumorigenesis in mouse models. We then assessed the functional coherence of the resulting Apc-Cdkn1a network by engineering in vivo single node perturbations of the network: mouse models mutated individually at Apc (Apc1638N+/2) or Cdkn1a (Cdkn1a-/-), followed by measurements of protein and gene expression changes in intestinal epithelial tissue. We hypothesized that if the predicted network is biologically coherent (functional), then the predicted nodes should associate more specifically with dysregulated genes and proteins than stochastically selected genes and proteins. The predicted Apc-Cdkn1a network was significantly perturbed at the mRNAlevel by both single gene knockouts, and the predictions were also strongly supported based on physical proximity and mRNA coexpression of proteomic targets. These results support the functional coherence of the proposed Apc-Cdkn1a network and also demonstrate how network-based predictions can be statistically tested using high-throughput biological data.

Original languageEnglish (US)
Article numbere12497
Pages (from-to)1-12
Number of pages12
JournalPLoS One
Volume5
Issue number9
DOIs
StatePublished - 2010

Fingerprint

Intestinal Neoplasms
Genes
neoplasms
prediction
Testing
Proteins
genes
testing
Gene Knockout Techniques
Neoplasm Genes
Intestinal Mucosa
animal models
Proteomics
Colorectal Neoplasms
somatic mutation
Electric network analysis
Carcinogenesis
Gene expression
proteins
gene targeting

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Patel, V. N., Bebek, G., Mariadason, J. M., Wang, D., Augenlicht, L. H., & Chance, M. R. (2010). Prediction and testing of biological networks underlying intestinal cancer. PLoS One, 5(9), 1-12. [e12497]. https://doi.org/10.1371/journal.pone.0012497

Prediction and testing of biological networks underlying intestinal cancer. / Patel, Vishal N.; Bebek, Gurkan; Mariadason, John M.; Wang, Donghai; Augenlicht, Leonard H.; Chance, Mark R.

In: PLoS One, Vol. 5, No. 9, e12497, 2010, p. 1-12.

Research output: Contribution to journalArticle

Patel, VN, Bebek, G, Mariadason, JM, Wang, D, Augenlicht, LH & Chance, MR 2010, 'Prediction and testing of biological networks underlying intestinal cancer', PLoS One, vol. 5, no. 9, e12497, pp. 1-12. https://doi.org/10.1371/journal.pone.0012497
Patel, Vishal N. ; Bebek, Gurkan ; Mariadason, John M. ; Wang, Donghai ; Augenlicht, Leonard H. ; Chance, Mark R. / Prediction and testing of biological networks underlying intestinal cancer. In: PLoS One. 2010 ; Vol. 5, No. 9. pp. 1-12.
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