From genome to phenome: Predicting multiple cancer phenotypes based on somatic genomic alterations via the genomic impact transformer.

ABSTRACT: Cancers are mainly caused by somatic genomic alterations (SGAs) that perturb cellular signaling systems and eventually activate oncogenic processes. Therefore, understanding the functional impact of SGAs is a fundamental task in cancer biology and precision oncology. Here, we present a deep neural network model with encoder-decoder architecture, referred to as genomic impact transformer (GIT), to infer the functional impact of SGAs on cellular signaling systems through modeling the statistical relationships between SGA events and differentially expressed genes (DEGs) in tumors. The model utilizes a multi-head self-attention mechanism to identify SGAs that likely cause DEGs, or in other words, differentiating potential driver SGAs from passenger ones in a tumor. GIT model learns a vector (gene embedding) as an abstract representation of functional impact for each SGA-affected gene. Given SGAs of a tumor, the model can instantiate the states of the hidden layer, providing an abstract representation (tumor embedding) reflecting characteristics of perturbed molecular/cellular processes in the tumor, which in turn can be used to predict multiple phenotypes. We apply the GIT model to 4,468 tumors profiled by The Cancer Genome Atlas (TCGA) project. The attention mechanism enables the model to better capture the statistical relationship between SGAs and DEGs than conventional methods, and distinguishes cancer drivers from passengers. The learned gene embeddings capture the functional similarity of SGAs perturbing common pathways. The tumor embeddings are shown to be useful for tumor status representation, and phenotype prediction including patient survival time and drug response of cancer cell lines.

SUBMITTER: Tao Y 

PROVIDER: S-EPMC6932864 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature