Abstract 173: Efficient representations of tumor diversity with paired DNA-RNA aberrations

Abstract In this work we develop a framework which allows for a systematic analysis of joint DNA and putative downstream RNA effects in cancer data cohorts. Using the Reactome database, we extract gene pairs that are linked by known mechanistic connections. Such pairs, which we refer to as 'Source Target Pairs' or STPs, consist of a source gene for which we examine aberrant activity in the DNA profile, and a target gene that is affected by said source gene, for which we examine aberrant activity in the RNA profile. Using TCGA data for six different cancer types (breast, colon, kidney, liver, lung and prostate), we use mutation and copy number variation information to compile DNA aberrant activity data. For the same cancer cohorts, we use RNASeq gene expression data to quantify RNA aberrant activity via the previous 'divergence' method we have developed. In the divergence framework, normal samples from the same cancer are used to estimate a normal range of expression for target genes of interest and deviation from the normal range is assumed to indicate aberrant activity which may result from upstream DNA aberrations. Then for a given sample, an STP can be represented as a binary variable, indicating presence or absence of joint DNA-RNA aberrant activity. We utilize integer programming to discover a small set of such STPs for each cancer type such that every sample displays aberrant activity in at least one STP. We refer to these reduced STP configurations as 'minimal coverings' of that cancer. These configurations then allow for the quantification of heterogeneity for that cancer type, as well as for phenotypical groups of interest. This is made possible due to the fact that sample to sample variability can be compared via the entropy of the distribution of the minimal covering, where the small number of STPs in such a configuration makes the computation more tractable. Our results reveal many known putative drivers of cancer, as well as identify some novel genes of interest for further consideration. Comparison of heterogeneity across phenotypes of interest show higher entropy in more pathological phenotypes, indicating increasing heterogeneity with severity of disease. Citation Format: Qian Ke, Wikum Dinalankara, Laurent Younes, Donald Geman, Luigi Marchionni. Efficient representations of tumor diversity with paired DNA-RNA aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 173.