.. role:: opt Terminology !!!!!!!!!!! .. _gene-fusions: Gene Fusions @@@@@@@@@@@@ Gene fusions are a complex class of genomic variation that may be characterized by a broad range of relevant attributes with varying specificity. :opt:`A gene fusion is the joining of two or more genes resulting in a` :ref:`chimeric transcript` :opt:`and/or a novel interaction between a rearranged regulatory element with the expression of a partner gene product (a` :ref:`regulatory fusion`\ :opt:`).` Genetic variations involving :ref:`rearrangements` within the same gene (e.g. internal tandem duplications), and transcript alterations due to splice site variants, have similar structural properties (i.e. novel adjoining :ref:`transcript segments`) but are not considered gene fusions as they do not involve multiple genes. Importantly, gene fusions are also distinct from :ref:`rearrangements`, though these concepts are often conflated due to the role of DNA rearrangements in creating gene fusions. The two primary classes of gene fusions–:ref:`chimeric-fusions` and :ref:`regulatory-fusions`–are not mutually exclusive classes, as some fusions (such as promoter-swap fusions) may be defined either in the context of their regulatory elements or by their chimeric gene product. .. _chimeric-fusions: Chimeric Transcript Fusions ########################### Chimeric transcript fusions are often driven by DNA rearrangements involving two gene loci, resulting in the concatenation of segments from each into a single transcript. This class of fusions is exemplified by well-known clinically-relevant gene fusions such as BCR::ABL1. :opt:`A chimeric transcript is a transcript (RNA molecule) composed of` :ref:`transcript segments` :opt:`from two or more genes.` Other biologically-relevant chimeric transcript fusions may be driven by RNA processing mechanisms in lieu of DNA rearrangements. One such mechanism is read-through transcription (e.g. CTSD-IFITM10), also known as *tandem chimerism*, where consecutive genes on a chromosome strand are transcribed as a single molecule prior to splicing `[Akiva P, et al.]`_. Another mechanism is trans-splicing (e.g. trans-spliced JAZF1::JJAZ1 `[Li H, et al.]`_), where two distinct transcripts are spliced together during processing. .. _read-through-note: .. admonition:: Note: the special case of read-through fusions Descriptions of read-through transcripts typically involve genes that are adjacent to one another in a reference genome assembly. The duality of the component genes encoding both independent and joint transcripts has resulted in authorities such as HGNC and CCDS creating read-through gene concepts, following a GENE1-GENE2 naming convention. *However, read-through transcripts generated from genes brought into proximity by a rearrangement should be annotated with a double-colon instead of a hyphen.* In practice, it is rare to report on read-through events, as these events are common and typically have little known biological relevance `[Mudge J]`_. .. _[Li H, et al.]: https://www.science.org/doi/abs/10.1126/science.1156725 .. _[Mudge J]: https://www.ensembl.info/2019/02/11/annotating-readthrough-transcription-in-ensembl/#:~:text=there%20is%20very,the%20downstream%20locus. .. _[Akiva P, et al.]: https://genome.cshlp.org/content/16/1/30.full .. figure:: images/chimeric-transcripts.png :scale: 50% Gene fusions typically result in chimeric transcripts between two genes, which (for coding transcripts) often result in novel protein sequences. These chimeric transcripts are often caused by DNA rearrangements that bring the DNA elements contributing to a gene fusion into close proximity with one another. .. _regulatory-fusions: Regulatory Fusions ################## Regulatory fusions are characterized by the rearrangement of regulatory elements from one gene near a second gene, typically resulting in the increased gene product expression of the second gene. This class of gene fusions should be described using the :ref:`regulatory-nomenclature`, and includes promoter-swapping gene fusions such as reg_p\@TMPRSS2::ERG, as well as enhancer-driven gene fusions such as reg_e\@GATA2::EVI1. :opt:`A regulatory fusion is the novel interaction of a regulatory element brought into proximity of a partner gene by a` :ref:`genomic rearrangement`\ :opt:`, modulating gene product expression of the partner gene.` .. figure:: images/regulatory-fusions.png :scale: 50% Gene fusions may be regulatory in nature, where a rearranged promoter or nearby enhancer element drives overexpression of the partner gene. .. _fusion-contexts: Gene Fusion Contexts @@@@@@@@@@@@@@@@@@@@ Determining the salient elements for a gene fusion is dependent upon the context in which the gene fusion is being described, whether it describes an assayed fusion event from a sample (:ref:`assayed-fusions`) or an aggregate context described in biomedical literature or knowledgebases (:ref:`categorical-fusions`). This specification provide recommendations for characterizing gene fusions in each context. .. _assayed-fusions: Assayed Gene Fusions #################### Assayed gene fusions from biological specimens are directly detected using RNA-based gene fusion assays, or alternatively may be inferred from genomic rearrangements detected by whole genome sequencing or cytogenomic assays in the context of informative phenotypic biomarkers. For example, an EWSR1 fusion is often inferred by breakapart FISH assay when a neoplasm is diagnosed or suspected to be Ewing sarcoma/primitive neuroectodermal tumor by immunohistochemical and/or morphological analysis. .. _categorical-fusions: Categorical Gene Fusions ######################## In contrast, categorical gene fusions are generalized concepts representing a class of fusions by their shared attributes, such as retained or lost regulatory elements and/or functional domains, and are typically curated from the biomedical literature for use in genomic knowledgebases. Example categorical gene fusions include: - EWSR1 as a known 5' gene fusion partner that joins one of many putative 3' partner genes - ALK as a 3' gene fusion partner with a retained kinase domain, which joins one of many putative 5' partner genes - The class of BCR::ABL1 fusions involving multiple possible junctions between exons from the constituent BCR and ABL1 transcripts Related Variant Types @@@@@@@@@@@@@@@@@@@@@ Gene fusions are closely related to, but distinct from many related types of genomic variation. Those types are described in this section for contrast, but are not otherwise discussed in the Gene Fusion Guidelines. .. _rearrangements: DNA Rearrangements ################## Gene fusions are typically driven by DNA rearrangements within the genome. DNA rearrangements can move genetic elements to new locations in the genome, leading to potential gene fusion events. Gene fusions may also be created by post-transcriptional splicing events. .. figure:: images/rearrangements.png :scale: 50% DNA Rearrangements include translocations, deletions, duplications, and inversions, each of which has the potential to move genes near one another and create gene fusions. .. _itd: Internal Tandem Duplications ############################ Internal tandem duplications are repeated transcribed elements within a gene as a result of focal duplications. Some gene fusion callers also call internal tandem duplications. However, gene fusions are defined by the interaction between **two or more genes**, therefore internal tandem duplications are not gene fusions and guidelines for characterizing them are out of scope for this work.