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Center for Computational Systems Medicine
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Fusion Gene and Fusion Protein Summary

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Fusion Amino Acid Sequences (multiple BPs and multiple gene isoforms)

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Fusion Protein Breakpoint Sequences - (for the Screening of the FusionNeoAntigens)

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Potential FusionNeoAntigens in HLA I - (netMHCpan v4.1 + deepHLApan v1.1)

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Potential FusionNeoAntigens in HLA II - (netMHCIIpan v4.1)

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Fusion Breakpoint 14 AA Peptide Structure - (RoseTTAFold)

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D - (Glide)

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Vaccine Design for the FusionNeoAntigens (RNA/protein sequences)

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Potential target of CAR-T therapy development

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Information on the samples that have these potential fusion neoantigens

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Fusion Protein Targeting Drugs - (Manual Curation)

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Fusion Protein Related diseases - (Manual Curation)

Fusion Protein:SETD2-KIF9

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: SETD2-KIF9
FusionPDB ID: 80871
FusionGDB2.0 ID: 80871
HgeneTgene
Gene symbol

SETD2

KIF9

Gene ID

29072

64147

Gene nameSET domain containing 2, histone lysine methyltransferasekinesin family member 9
SynonymsHBP231|HIF-1|HIP-1|HSPC069|HYPB|KMT3A|LLS|SET2|p231HBP-
Cytomap

3p21.31

3p21.31

Type of geneprotein-codingprotein-coding
Descriptionhistone-lysine N-methyltransferase SETD2SET domain containing 2huntingtin interacting protein 1huntingtin yeast partner Bhuntingtin-interacting protein Blysine N-methyltransferase 3Aprotein-lysine N-methyltransferase SETD2kinesin-like protein KIF9kinesin protein 9
Modification date2020031520200313
UniProtAcc

Q9BYW2

Main function of 5'-partner protein: FUNCTION: Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426). {ECO:0000250|UniProtKB:E9Q5F9, ECO:0000269|PubMed:16118227, ECO:0000269|PubMed:19141475, ECO:0000269|PubMed:21526191, ECO:0000269|PubMed:21792193, ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:23325844, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24843002, ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}.; FUNCTION: (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression. {ECO:0000269|PubMed:11461154}.

Q9HAQ2

Main function of 5'-partner protein:
Ensembl transtripts involved in fusion geneENST idsENST00000409792, ENST00000492397, 
ENST00000352910, ENST00000425452, 
ENST00000425853, ENST00000432493, 
ENST00000487440, ENST00000265529, 
ENST00000335044, ENST00000444589, 
ENST00000452770, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score27 X 19 X 16=82085 X 5 X 4=100
# samples 416
** MAII scorelog2(41/8208*10)=-4.32333491610161
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
log2(6/100*10)=-0.736965594166206
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: SETD2 [Title/Abstract] AND KIF9 [Title/Abstract] AND fusion [Title/Abstract]

Fusion neoantigen context

PubMed: SETD2 [Title/Abstract] AND KIF9 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)SETD2(47205344)-KIF9(47289576), # samples:5
Anticipated loss of major functional domain due to fusion event.SETD2-KIF9 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF.
SETD2-KIF9 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF.
* DoF score (Degree of Frequency) = # partners X # break points X # cancer types
** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10)

check button Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez
PartnerGeneGO IDGO termPubMed ID
HgeneSETD2

GO:0010569

regulation of double-strand break repair via homologous recombination

24843002

HgeneSETD2

GO:0018023

peptidyl-lysine trimethylation

27518565

HgeneSETD2

GO:0018026

peptidyl-lysine monomethylation

28753426

HgeneSETD2

GO:0032465

regulation of cytokinesis

27518565

HgeneSETD2

GO:0032727

positive regulation of interferon-alpha production

28753426

HgeneSETD2

GO:0034340

response to type I interferon

28753426

HgeneSETD2

GO:0051607

defense response to virus

28753426

HgeneSETD2

GO:0097198

histone H3-K36 trimethylation

23043551|24843002|26002201|27474439|28753426

HgeneSETD2

GO:0097676

histone H3-K36 dimethylation

26002201

HgeneSETD2

GO:1902850

microtubule cytoskeleton organization involved in mitosis

27518565

HgeneSETD2

GO:1905634

regulation of protein localization to chromatin

24843002



check button Four levels of functional features of fusion genes
Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr3:47205344/chr3:47289576)
- FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels.
- How to search
1. Put your fusion gene symbol.
2. Press the tab key until there will be shown the breakpoint information filled.
4. Go down and press 'Search' tab twice.
4. Go down to have the hyperlink of the search result.
5. Click the hyperlink.
6. See the FGviewer result for your fusion gene.
FGviewer

check buttonRetention analysis results of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features, are available here.

check buttonFusion gene breakpoints across SETD2 (5'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure

check buttonFusion gene breakpoints across KIF9 (3'-gene)
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.
all structure


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Fusion Amino Acid Sequences


check buttonFusion information from ORFfinder translation from full-length transcript sequence from FusionPDB.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandSeq length
(transcript)
BP loci
(transcript)
Predicted start
(transcript)
Predicted stop
(transcript)
Seq length
(amino acids)
ENST00000409792SETD2chr347205344-ENST00000335044KIF9chr347316980-30201141892393734
ENST00000409792SETD2chr347205344-ENST00000265529KIF9chr347316980-26511141892393734
ENST00000409792SETD2chr347205344-ENST00000444589KIF9chr347316980-24541141892198669
ENST00000409792SETD2chr347205344-ENST00000452770KIF9chr347316980-23941141892393734

check buttonDeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated.
HenstTenstHgeneHchrHbpHstrandTgeneTchrTbpTstrandNo-coding scoreCoding score
ENST00000409792ENST00000335044SETD2chr347205344-KIF9chr347316980-0.0114366970.9885633
ENST00000409792ENST00000265529SETD2chr347205344-KIF9chr347316980-0.0092296060.99077034
ENST00000409792ENST00000444589SETD2chr347205344-KIF9chr347316980-0.0074690590.9925309
ENST00000409792ENST00000452770SETD2chr347205344-KIF9chr347316980-0.0085781230.9914219

check button Predicted full-length fusion amino acid sequences. For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among all the predicted ones.

Get the fusion protein sequences from here.

Fusion protein sequence information is available in the fasta format.
>FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP

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Fusion Protein Breakpoint Sequences for SETD2-KIF9

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide

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Potential FusionNeoAntigen Information of SETD2-KIF9 in HLA I

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.

check button Potential FusionNeoAntigen Information
* We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5)
Fusion geneHchrHbpTgeneTchrTbpHLA IFusionNeoAntigen peptideBinding scoreImmunogenic scoreNeoantigen start (at BP 13)Neoantigen end (at BP 13)

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Potential FusionNeoAntigen Information of SETD2-KIF9 in HLA II

check button Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific.

check button Potential FusionNeoAntigen Information
* We used NetMHCIIpan v4.1 (%rank<0.5).
Fusion geneHchrHbpTgeneTchrTbpHLA IIFusionNeoAntigen peptideNeoantigen start (at BP 13)Neoantigen end (at BP 13)

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Fusion breakpoint peptide structures of SETD2-KIF9

check button3D structures of the fusion breakpoint peptide of 14AA sequence that have potential fusion neoantigens
* The minimum length of the amino acid sequence in RoseTTAFold is 14AA. Here, we predicted the 14AA fusion protein breakpoint sequence not the fusion neoantigen peptide, which is shorter than 14 AA.

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of SETD2-KIF9

check buttonVirtual screening between 25 HLAs (from PDB) and FusionNeoAntigens
* We used Glide to predict the interaction between HLAs and neoantigens.
HLA allelePDB IDFile nameBPseqDocking scoreGlide score

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Vaccine Design for the FusionNeoAntigens of SETD2-KIF9

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptide sequenceFusionNeoAntigen RNA sequence

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence

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Information of the samples that have these potential fusion neoantigens of SETD2-KIF9

check button These samples were reported as having these fusion breakpoints. For individual breakpoints, we checked the open reading frames considering multiple gene isoforms and chose the in-frame fusion genes only. Then, we made fusion protein sequences and predicted the fusion neoantigens. These fusion-positive samples may have these potential fusion neoantigens.
Cancer typeFusion geneHchrHbpHenstTchrTbpTenstSample

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Potential target of CAR-T therapy development for SETD2-KIF9

check button Predicted 3D structure. We used RoseTTAFold.

check buttonRetention analysis result of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, to provide the retention of the transmembrane domain, we only show the protein feature retention information of those transmembrane features


* Minus value of BPloci means that the break point is located before the CDS.
- In-frame and retained 'Transmembrane'.
PartnerGeneHbpTbpENSTStrandBPexonTotalExonProtein feature loci*BPlociTotalLenProtein featureProtein feature note

check button Subcellular localization prediction of the transmembrane domain retained fusion proteins
* We used DeepLoc 1.0. The order of the X-axis of the barplot is as follows: Entry_ID, Localization, Type, Nucleus, Cytoplasm, Extracellular, Mitochondrion, Cell_membrane, Endoplasmic_reticulum, Plastid, Golgi.apparatus, Lysosome.Vacuole, Peroxisome. Y-axis is the output score of DeepLoc. Clicking the image will open a new tab with a large image.
HgeneHchrHbpHenstTgeneTchrTbpTenstDeepLoc result

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Related Drugs to SETD2-KIF9

check button Drugs used for this fusion-positive patient.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDrugSourcePMID

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Related Diseases to SETD2-KIF9

check button Diseases that have this fusion gene.
(Manual curation of PubMed, 04-30-2022 + MyCancerGenome)
HgeneTgeneDiseaseSourcePMID

check button Diseases associated with fusion partners.
(DisGeNet 4.0)
PartnerGeneDisease IDDisease name# pubmedsSource
HgeneSETD2C0279702Conventional (Clear Cell) Renal Cell Carcinoma6CGI;CTD_human;UNIPROT
HgeneSETD2C4085873LUSCAN-LUMISH SYNDROME4CTD_human;GENOMICS_ENGLAND;UNIPROT
HgeneSETD2C0007134Renal Cell Carcinoma2CTD_human
HgeneSETD2C0023467Leukemia, Myelocytic, Acute2UNIPROT
HgeneSETD2C1266042Chromophobe Renal Cell Carcinoma2CTD_human
HgeneSETD2C1266043Sarcomatoid Renal Cell Carcinoma2CTD_human
HgeneSETD2C1266044Collecting Duct Carcinoma of the Kidney2CTD_human
HgeneSETD2C1306837Papillary Renal Cell Carcinoma2CTD_human
HgeneSETD2C1961102Precursor Cell Lymphoblastic Leukemia Lymphoma2UNIPROT
HgeneSETD2C0006142Malignant neoplasm of breast1CTD_human
HgeneSETD2C0010606Adenoid Cystic Carcinoma1CTD_human
HgeneSETD2C0010701Phyllodes Tumor1CTD_human
HgeneSETD2C0023418leukemia1CTD_human
HgeneSETD2C0033578Prostatic Neoplasms1CTD_human
HgeneSETD2C0175695Sotos' syndrome1ORPHANET
HgeneSETD2C0206656Embryonal Rhabdomyosarcoma1CTD_human
HgeneSETD2C0345967Malignant mesothelioma1CTD_human
HgeneSETD2C0376358Malignant neoplasm of prostate1CTD_human
HgeneSETD2C0600066Malignant Cystosarcoma Phyllodes1CTD_human
HgeneSETD2C0678222Breast Carcinoma1CTD_human
HgeneSETD2C0920269Microsatellite Instability1CTD_human
HgeneSETD2C1257931Mammary Neoplasms, Human1CTD_human
HgeneSETD2C1458155Mammary Neoplasms1CTD_human
HgeneSETD2C1535926Neurodevelopmental Disorders1CTD_human
HgeneSETD2C1721098Replication Error Phenotype1CTD_human
HgeneSETD2C3714756Intellectual Disability1GENOMICS_ENGLAND
HgeneSETD2C4704874Mammary Carcinoma, Human1CTD_human