Abstract
Oncogenic gene fusions are estimated to account for up-to 20% of cancer morbidity. Recently sequence-level studies have established oncofusions throughout all tissue types. However, the functional implications of the identified oncofusions have often not been investigated. In this study, identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in detail. Of the 28,863 oncofusions, we found almost 30% are expected to produce functional proteins with features from both parent genes. Kinases and transcription factors were the main gene families of the protein producing fusions. Considering their role as initiators, actors, and termination points of cellular signaling pathways, we focused our in-depth analyses on them. Domain architecture of the fusions and their wild-type interactors suggests that abnormal molecular context of protein domains caused by fusion events may unlock the oncogenic potential of the wild type counterparts of the fusion proteins. To understand overall oncofusion effects, we performed differential expression analysis using TCGA cancer project samples. Results indicated oncofusion-specific alterations in gene expression levels, and lower expression levels of components of key cellular pathways, in particular signal transduction and transcription regulation. The sum of results suggests that kinase and transcription factor oncofusions deregulate cellular signaling, possibly via acquiring novel functions.
Highlights
Sequences, obtaining androgen receptor (AR)-responsive e xpression[11]
To characterize the proteins produced by known OFs in the TCGA dataset, which currently contains data from 33 different cancer projects, we launched an analysis to understand the potential functional space of the protein producing fusions (Fig. 1B), and especially those that involve either a protein kinases (PKs) or a transcription factors (TFs), or both (PK-TF fusions)
Examining the resulting protein producing OF set, we noticed an abundance of those involving PK or TF
Summary
Sequences, obtaining androgen receptor (AR)-responsive e xpression[11]. The current understanding favors the aberrant gene function model rather than promoter-induced over-expression. NGS has provided enough detailed sequence information of the fusion breakpoints allowing us to initiate systems-level research on human oncofusions. Various algorithms have been developed to mine OFs from large cancer datasets such as TCGA. Oncofusions that involve PKs and TFs were selected from the data produced by DEEPEST applied to the TCGA dataset. An unexpectedly large number of PKs and TFs have been found to be mutationally activated or have increased expression due to gene amplification or translocation in cancer[6]. Fusions predicted to produce in-frame proteins were analyzed to understand the protein-level implications of fusion events. The fusions were analyzed from the perspective of their domain architecture to understand likely modes of action of the novel proteins. Multiple cellular signaling pathways were found to intersect with major subsets of these fusions, and multiple individual key interactors, such as NTRK1 with over 200 and EGFR with over 100 interacting fusions, were identified as potential targets of interest
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