May 6, 2014

Cooperation between Noncanonical Ras Network Mutations in Cancer

BioRxiv : the Preprint Server for Biology
Edward C StitesKodi S Ravichandran


Cancer develops after the acquisition of a collection of mutations that together create the ‘cancer phenotype’. How collections of mutations work together within a cell, and whether there is selection for certain combinations of mutations, are not well understood. Using a Ras signaling network mathematical model we tested potential synergistic combinations within the Ras network. Intriguingly, our modeling, including a “ computational random mutagenesis” approach, and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the effects of mutations in multiple other components of the Ras pathway, including weakly activating, noncanonical, Ras mutants. Since conventional wisdom holds that mutations within the same pathway do not co-occur, it was surprising that modeling and experiments both suggested a functional benefit for co-occurring Ras pathway mutations. Furthermore, we analyzed >3900 sequenced cancer specimens from the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) and we uncovered an increased rate of co-occurrence between mutations the model predicted could display synergy. Overall, these data suggest that selective combinations of Ras pathway mutations could s...Continue Reading

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Mentioned in this Paper

Biochemical Pathway
Tumor Suppressor Genes
Tumor Cells, Malignant
Genomic DNA
Mutagenesis Procedure
Genomic Instability
Malignant Neoplasms

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