Abstract
Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which have been seen in approximately 50 % of prostate cancers, several other common solid cancers have been shown to harbor recurrent gene fusions at low frequencies. On the other hand, many gene fusions involving oncogenes, such as those encoding ALK, RAF or FGFR kinase families, have been detected across multiple different epithelial carcinomas. Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful. Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1–4, and NOTCH1–3 have immediate implications for precision medicine across tissue types. Thus, ongoing cancer genomic and transcriptomic analyses for clinical sequencing need to delineate the landscape of gene fusions. Prioritization of potential oncogenic “drivers” from “passenger” fusions, and functional characterization of potentially actionable gene fusions across diverse tissue types, will help translate these findings into clinical applications. Here, we review recent advances in gene fusion discovery and the prospects for medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0252-1) contains supplementary material, which is available to authorized users.
Highlights
Recurrent chromosomal rearrangements in cancers have been described for over half a century [1, 2]
Perspectives and discussion Genomic or transcriptomic sequencing has virtually supplanted molecular and cytogenetic techniques as the primary modality for discovery of gene fusions, and detection of gene fusions is increasingly incorporated into the standard workflow for genomic characterization of tumors in both research and clinical settings
Transcriptome sequencing has been useful in helping to identify expressed gene fusions based on evidence of the fusion of exon boundaries, but putative promoter fusions that do not generate chimeric transcripts are likely to go undetected
Summary
Recurrent chromosomal rearrangements in cancers have been described for over half a century [1, 2]. A large number of fusions display recurrence of a fusion gene in combination with multiple different partners; for example, BRAF/RAF1 [76, 79, 82, 83] and FGFR1/2/3 [88,89,90,91,92,93,94] are fused to several different 5′ partners across different tissue types (Additional file 1) This heterogeneity is likely reflective of the diverse tissue–physiological milieu in which these oncogenes impart selective advantage to the cancer cells. Analysis of mRNA sequencing data from the TCGA compendium, comprising 4366 primary tumor samples from 13 tissue types, revealed kinase fusions involving ALK, ROS, RET, NTRK, and FGFR gene families, which were detected in several types of cancer: bladder carcinoma (3.3 %), glioblastoma (4.4 %), head and neck cancer (1.0 %), low-grade glioma (1.5 %), lung adenocarcinoma (1.6 %), lung squamous cell carcinoma (2.3 %), and thyroid carcinoma (8.7 %) [89]. TFE3, which belongs to the MITF/TFE family of basic helix-loop-helix leucine zipper transcription factors, is involved in TGF-βinduced transcription, and has important roles in cell
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