Somatic mutations modulate ceRNA drivers of tumorigenesis. J. He1,2,3, H.-S. Chiu4, P. Sumazin4, A. Califano1,2,3 1) Department of Systems Biology, Columbia University, New York, NY; 2) Center for Computational Biology and Bioinformatics, Columbia University, New York, NY; 3) Department of Biomedical Informatics, Columbia University, New York, NY; 4) Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.

   Pan-cancer studies have shown that competitive endogenous RNA (ceRNA) networks can cooperate with chromosome instability and abnormal DNA methylation in tumors to dysregulate tumor suppressors and oncogenes. However, ceRNA cooperative association with mutations in cancer has not been studied. Integrating data from TCGA and ENCODE, we show that the cooperation between ceRNA interactions and mutations of unknown function contribute to the dysregulation of cancer genes. We integrated ceRNA networks and mutations in an attempt to mechanistically recover missing genomic variability of cancer genes in TCGA breast cancer biopsies. Genes have missing genomic variability in a tumor dataset when their dysregulation cannot be explained through profiling of their DNA locus. Using a group lasso regression model we showed that ceRNA drivers cooperating with somatic mutations, CNV, and methylation, could account for a large fraction of the missing genomic variability of cancer genes in breast cancer. Moreover, using a greedy-forward optimization algorithm, we identified ceRNA driver mutations that could potentially drive tumorigenesis through the ceRNA mechanism. Furthermore, we showed that driver ceRNA mutations are enriched in known and predicted binding sites of transcription factors and microRNAs. In summary, our results suggest that somatic mutations, often of unknown function, cooperate with ceRNA regulators to alter the expression of cancer genes in breast cancer tumors.

You may contact the first author (during and after the meeting) at