Methods for detecting co-mutated pathways in cancer samples to inform treatment selection

Jiang, T.; Shaham, U.; Parisi, F.; Halaban, R.; Safonov, A.; Kluger, H.; Weissman, S.; Chang, J.; Kluger, Y.

doi:10.1101/082552

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bioRxiv · 10.1101/082552

Methods for detecting co-mutated pathways in cancer samples to inform treatment selection

Jiang, T.·Shaham, U.·Parisi, F.·Halaban, R.·Safonov, A.·Kluger, H.·Weissman, S.·Chang, J.·Kluger, Y.

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Abstract

Tumor genomes evolve through a selection of mutations. These mutations may complement each other to promote tumorigenesis. To better understand the functional interactions of different processes in cancer, we studied mutation data of a set of tumors and identified significantly co-mutated pathways. Fishers exact test is a standard approach that can be used to assess the significance of the joint dysregulation of pathways pairs across a patient population. We developed a robust test to identify co-occurrence using DNA mutations, which overcomes deficiencies of the Fishers exact test by taking into account the large variability in overall mutation load and sequencing depth. Applying our method to a study of six common cancer types, we identify enrichment of co-mutated signal transduction pathways such as IP3 synthesis and PI3K and pairs of co-mutated pathways involving other processes such as immunity and development. We observed enrichment of clonal co-mutation of the proteasome and apoptosis pathways in colorectal cancer, which suggests potential mechanisms for immune evasion.

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Jiang, T., Shaham, U., Parisi, F., Halaban, R., Safonov, A., Kluger, H., Weissman, S., Chang, J., Kluger, Y.. 2016-10-22. Methods for detecting co-mutated pathways in cancer samples to inform treatment selection. https://doi.org/10.1101/082552

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