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Abstract
Genomic rearrangements involving transcription factors (TFs) can form fusion proteins resulting in either enhanced, weakened, or even loss of TF activity. Functional domain (FD) retention is a critical factor in the activity of transcription factor fusion genes (TFFGs). A systematic investigation of FD retention in TFFGs and their outcome (e.g. expression changes) in a pan-cancer study has not yet been completed. Here, we examined the FD retention status in 386 TFFGs across 13 major cancer types and identified 83 TFFGs involving 67 TFs that retained FDs. To measure the potential biological relevance of TFs in TFFGs, we introduced a Major Active Isofusion Index (MAII) and built a prioritized TFFG network using MAII scores and the observed frequency of fusion positive samples. Interestingly, the four TFFGs (PML-RARA, RUNX1-RUNX1T1, TMPRSS2-ERG, and SFPQ-TFE3) with the highest MAII scores showed 50 differentially expressed target genes (DETGs) in fusion-positive versus fusion-negative cancer samples. DETG analysis revealed that they were involved in tumorigenesis-related processes in each cancer type. PLAU, which encodes plasminogen activator urokinase and serves as a biomarker for tumor invasion, was found to be consistently activated in the samples with the highest MAII scores. Among the 50 DETGs, 21 were drug targetable genes. Fourteen of these 21 DETGs were expressed in acute myeloid leukemia (AML) samples. Accordingly, we constructed an AML-specific TFFG network, which included 38 DETGs in RUNX1-RUNX1T1 or PML-RARA positive samples. In summary, this study revealed several TFFGs and their potential target genes, and provided insights into the clinical implications of TFFGs.
Highlights
Chromosomal aberrations leading to gene fusions occur frequently in cancer cells
We investigated the retention of Functional domain (FD) by translating the fusion transcripts into amino acid sequences and searching for the presence of 34 protein features from UniProt
transcription factor fusion genes (TFFGs) significantly retained 14 out of 34 protein features at a relatively higher frequency than non-TFFGs; these domains are: ‘site’, ‘compositional bias’, ‘cross-link’, ‘zinc finger’, ‘region’, ‘DNA binding’, ‘mutagenesis’, ‘modified residue’, ‘motif’, ‘helix’, ‘turn’, ‘initiator methionine’, ‘metal binding’, and ‘beta strand’. This result is consistent with previous reports that transcription factors (TFs) fusion proteins often contain several different protein domains such as a DNA-binding domains, domains that act in homo or hetero-dimerization, and domains that interact with chromatin remodeling components such as co-repressor molecules [11]. Among these FD-retained TFFGs, we focused on the domains with TF activity such as ‘calcium binding’, ‘DNA binding’, ‘domain’, ‘metal binding’, ‘motif’, ‘nucleotide binding’, and ‘zinc finger’
Summary
Chromosomal aberrations leading to gene fusions occur frequently in cancer cells. Gene fusions play critical roles in tumorigenesis, can aid in cancer diagnosis, and serve as therapeutic targets. The recurrence of a fusion gene and retention of important functional domains (FDs) are important factors in assessing whether it plays an oncogenic role and has clinical relevance. Driver fusion genes typically retain functional domains (e.g., kinase domains or DNA-binding domains) [1, 2]. In our previous study [3], we performed a comprehensive analysis of kinase fusion genes that retain kinase domains and discovered features commonly present in recurrent kinase fusion genes. We performed a systematic annotation of transcription factor fusion genes (TFFGs), aiming to identify driver transcription factors (TFs) and fusion genes (FGs) across 13 major cancer types. TFFGs may enhance the activity or result in loss of function of a TF and its target genes. TFFGs are known for their www.impactjournals.com/oncotarget dominant-negative effects, supported by the observation of a higher frequency of DNA binding domains than transcriptional activation domains [4]
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