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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:ROS1-CD74

Fusion Gene and Fusion Protein Summary

check button Fusion gene summary
Fusion partner gene informationFusion gene name: ROS1-CD74
FusionPDB ID: 75411
FusionGDB2.0 ID: 75411
HgeneTgene
Gene symbol

ROS1

CD74

Gene ID

6098

972

Gene nameROS proto-oncogene 1, receptor tyrosine kinaseCD74 molecule
SynonymsMCF3|ROS|c-ros-1DHLAG|HLADG|II|Ia-GAMMA|p33
Cytomap

6q22.1

5q33.1

Type of geneprotein-codingprotein-coding
Descriptionproto-oncogene tyrosine-protein kinase ROSROS proto-oncogene 1 , receptor tyrosine kinasec-ros oncogene 1 , receptor tyrosine kinaseproto-oncogene c-Ros-1transmembrane tyrosine-specific protein kinasev-ros avian UR2 sarcoma virus oncogene homolog 1HLA class II histocompatibility antigen gamma chainCD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated)CD74 molecule, major histocompatibility complex, class II invariant chainHLA-DR antigens-associated
Modification date2020031420200313
UniProtAcc

P08922

Main function of 5'-partner protein: FUNCTION: Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2. {ECO:0000269|PubMed:11094073, ECO:0000269|PubMed:16885344}.

P04233

Main function of 5'-partner protein: FUNCTION: Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II takes place. Serves as cell surface receptor for the cytokine MIF.; FUNCTION: [Class-II-associated invariant chain peptide]: Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome. {ECO:0000269|PubMed:1448172}.; FUNCTION: [Isoform p41]: Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs). Has antiviral activity by stymieing the endosomal entry of Ebola virus and coronaviruses, including SARS-CoV-2 (PubMed:32855215). Disrupts cathepsin-mediated Ebola virus glycoprotein processing, which prevents viral fusion and entry. This antiviral activity is specific to p41 isoform (PubMed:32855215). {ECO:0000250|UniProtKB:P04441, ECO:0000269|PubMed:32855215}.
Ensembl transtripts involved in fusion geneENST idsENST00000368507, ENST00000368508, 
ENST00000009530, ENST00000353334, 
ENST00000377795, ENST00000524315, 
Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0)* DoF score3 X 4 X 1=1231 X 31 X 11=10571
# samples 439
** MAII scorelog2(4/12*10)=1.73696559416621
effective Gene in Pan-Cancer Fusion Genes (eGinPCFGs).
DoF>8 and MAII>0
log2(39/10571*10)=-4.76049392566144
possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs).
DoF>8 and MAII<0
Fusion gene context

PubMed: ROS1 [Title/Abstract] AND CD74 [Title/Abstract] AND fusion [Title/Abstract]

CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma (pmid: 23877438)
Fusion neoantigen context

PubMed: ROS1 [Title/Abstract] AND CD74 [Title/Abstract] AND neoantigen [Title/Abstract]

Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0)CD74(149784243)-ROS1(117645578), # samples:6
CD74(149784243)-ROS1(117645580), # samples:6
ROS1(117700222)-CD74(149782188), # samples:2
Anticipated loss of major functional domain due to fusion event.CD74-ROS1 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.
CD74-ROS1 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.
ROS1-CD74 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.
ROS1-CD74 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.
ROS1-CD74 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.
ROS1-CD74 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.
ROS1-CD74 seems lost the major protein functional domain in Hgene partner, which is a CGC due to the frame-shifted ORF.
ROS1-CD74 seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF.
ROS1-CD74 seems lost the major protein functional domain in Hgene partner, which is a kinase due to the frame-shifted ORF.
ROS1-CD74 seems lost the major protein functional domain in Tgene partner, which is a CGC due to the frame-shifted ORF.
ROS1-CD74 seems lost the major protein functional domain in Tgene partner, which is a IUPHAR drug target due to the frame-shifted 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
HgeneROS1

GO:0001558

regulation of cell growth

16885344

HgeneROS1

GO:0006468

protein phosphorylation

16885344

HgeneROS1

GO:0032006

regulation of TOR signaling

16885344

TgeneCD74

GO:0001516

prostaglandin biosynthetic process

12782713

TgeneCD74

GO:0001934

positive regulation of protein phosphorylation

24942581

TgeneCD74

GO:0002792

negative regulation of peptide secretion

19849849

TgeneCD74

GO:0033674

positive regulation of kinase activity

24942581

TgeneCD74

GO:0043066

negative regulation of apoptotic process

12782713

TgeneCD74

GO:0043123

positive regulation of I-kappaB kinase/NF-kappaB signaling

24942581

TgeneCD74

GO:0043410

positive regulation of MAPK cascade

24942581

TgeneCD74

GO:0043518

negative regulation of DNA damage response, signal transduction by p53 class mediator

17045821

TgeneCD74

GO:0045657

positive regulation of monocyte differentiation

24942581

TgeneCD74

GO:0045893

positive regulation of transcription, DNA-templated

24942581

TgeneCD74

GO:0046598

positive regulation of viral entry into host cell

24942581

TgeneCD74

GO:0050731

positive regulation of peptidyl-tyrosine phosphorylation

17045821

TgeneCD74

GO:0070374

positive regulation of ERK1 and ERK2 cascade

17045821|24942581



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/chr6:149784243/chr5:117645578)
- 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 ROS1 (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 CD74 (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)
ENST00000368508ROS1chr6117700222-ENST00000377795CD74chr5149782188-347327961993045948
ENST00000368507ROS1chr6117700222-ENST00000377795CD74chr5149782188-345827811993030943
ENST00000368508ROS1chr6117700221-ENST00000377795CD74chr5149782188-347327961993045948
ENST00000368507ROS1chr6117700221-ENST00000377795CD74chr5149782188-345827811993030943
ENST00000368508ROS1chr6117700221-ENST00000377795CD74chr5149782187-347327961993045948
ENST00000368507ROS1chr6117700221-ENST00000377795CD74chr5149782187-345827811993030943

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
ENST00000368508ENST00000377795ROS1chr6117700222-CD74chr5149782188-0.000461170.9995389
ENST00000368507ENST00000377795ROS1chr6117700222-CD74chr5149782188-0.0002970750.9997029
ENST00000368508ENST00000377795ROS1chr6117700221-CD74chr5149782188-0.000461170.9995389
ENST00000368507ENST00000377795ROS1chr6117700221-CD74chr5149782188-0.0002970750.9997029
ENST00000368508ENST00000377795ROS1chr6117700221-CD74chr5149782187-0.000461170.9995389
ENST00000368507ENST00000377795ROS1chr6117700221-CD74chr5149782187-0.0002970750.9997029

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 ROS1-CD74

check button +/-13 AA sequence from the breakpoints of the fusion protein sequences.
HgeneHchrHbpTgeneTchrTbpLength(fusion protein)BP in fusion proteinPeptide
ROS1chr6117700221CD74chr51497821872781860QCIHLYTAVLRGQRVTGTGGPVFWAG
ROS1chr6117700221CD74chr51497821872796865QCIHLYTAVLRGQRVTGTGGPVFWAG
ROS1chr6117700221CD74chr51497821882781860QCIHLYTAVLRGQRVTGTGGPVFWAG
ROS1chr6117700221CD74chr51497821882796865QCIHLYTAVLRGQRVTGTGGPVFWAG
ROS1chr6117700222CD74chr51497821882781860QCIHLYTAVLRGQRVTGTGGPVFWAG
ROS1chr6117700222CD74chr51497821882796865QCIHLYTAVLRGQRVTGTGGPVFWAG

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Potential FusionNeoAntigen Information of ROS1-CD74 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.
ROS1-CD74_117700221_149782187.msa

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)
ROS1-CD74chr6117700221chr51497821872781HLA-A68:24YTAVLRGQR0.99580.6467514
ROS1-CD74chr6117700221chr51497821872781HLA-A68:03YTAVLRGQR0.99350.6375514
ROS1-CD74chr6117700221chr51497821872781HLA-A66:01YTAVLRGQR0.98610.5547514
ROS1-CD74chr6117700221chr51497821872781HLA-A68:08YTAVLRGQR0.98240.639514
ROS1-CD74chr6117700221chr51497821872781HLA-A33:05YTAVLRGQR0.97130.5573514
ROS1-CD74chr6117700221chr51497821872781HLA-A33:01YTAVLRGQR0.97130.5573514
ROS1-CD74chr6117700221chr51497821872781HLA-A68:05YTAVLRGQR0.96510.6434514
ROS1-CD74chr6117700221chr51497821872781HLA-B51:01TAVLRGQRV0.95870.6264615
ROS1-CD74chr6117700221chr51497821872781HLA-A68:06YTAVLRGQR0.95470.6587514
ROS1-CD74chr6117700221chr51497821872781HLA-A66:03YTAVLRGQR0.84970.5109514
ROS1-CD74chr6117700221chr51497821872781HLA-A74:09HLYTAVLRGQR0.98090.8284314
ROS1-CD74chr6117700221chr51497821872781HLA-A74:11HLYTAVLRGQR0.98090.8284314
ROS1-CD74chr6117700221chr51497821872781HLA-A74:03HLYTAVLRGQR0.98090.8284314
ROS1-CD74chr6117700221chr51497821872781HLA-A68:01YTAVLRGQR0.99580.6467514
ROS1-CD74chr6117700221chr51497821872781HLA-A33:03YTAVLRGQR0.97480.515514
ROS1-CD74chr6117700221chr51497821872781HLA-C06:03TAVLRGQRV0.85810.9911615
ROS1-CD74chr6117700221chr51497821872781HLA-C12:04TAVLRGQRV0.85090.9909615
ROS1-CD74chr6117700221chr51497821872781HLA-C12:12TAVLRGQRV0.6690.9461615
ROS1-CD74chr6117700221chr51497821872781HLA-B51:21TAVLRGQRV0.95970.5113615
ROS1-CD74chr6117700221chr51497821872781HLA-C16:04TAVLRGQRV0.85960.9654615
ROS1-CD74chr6117700221chr51497821872781HLA-C12:03TAVLRGQRV0.60780.9794615
ROS1-CD74chr6117700221chr51497821872781HLA-A74:01HLYTAVLRGQR0.98090.8284314

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Potential FusionNeoAntigen Information of ROS1-CD74 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.
ROS1-CD74_117700221_149782187.msa

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)
ROS1-CD74chr6117700221chr51497821872781DRB1-1145IHLYTAVLRGQRVTG217
ROS1-CD74chr6117700221chr51497821872781DRB1-1164IHLYTAVLRGQRVTG217
ROS1-CD74chr6117700221chr51497821872781DRB5-0106QCIHLYTAVLRGQRV015
ROS1-CD74chr6117700221chr51497821872781DRB5-0202QCIHLYTAVLRGQRV015
ROS1-CD74chr6117700221chr51497821872781DRB5-0203QCIHLYTAVLRGQRV015
ROS1-CD74chr6117700221chr51497821872781DRB5-0204QCIHLYTAVLRGQRV015
ROS1-CD74chr6117700221chr51497821872781DRB5-0205QCIHLYTAVLRGQRV015

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Fusion breakpoint peptide structures of ROS1-CD74

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.
File nameBPseqHgeneTgeneHchrHbpTchrTbpAAlen
9260TAVLRGQRVTGTGGROS1CD74chr6117700221chr51497821872781

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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of ROS1-CD74

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
HLA-B14:023BVN9260TAVLRGQRVTGTGG-8.85616-8.96956
HLA-B14:023BVN9260TAVLRGQRVTGTGG-5.66423-6.69953
HLA-B52:013W399260TAVLRGQRVTGTGG-6.49489-6.60829
HLA-B52:013W399260TAVLRGQRVTGTGG-3.99785-5.03315
HLA-A11:014UQ29260TAVLRGQRVTGTGG-4.90759-5.94289
HLA-A24:025HGA9260TAVLRGQRVTGTGG-7.27887-7.39227
HLA-A24:025HGA9260TAVLRGQRVTGTGG-7.11524-8.15054
HLA-B27:056PYJ9260TAVLRGQRVTGTGG-6.11615-6.22955
HLA-B27:056PYJ9260TAVLRGQRVTGTGG-4.78818-5.82348
HLA-B44:053DX89260TAVLRGQRVTGTGG-7.22602-7.33942
HLA-B44:053DX89260TAVLRGQRVTGTGG-4.86671-5.90201

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Vaccine Design for the FusionNeoAntigens of ROS1-CD74

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
ROS1-CD74chr6117700221chr5149782187314HLYTAVLRGQRCCTGTACACAGCTGTTCTTCGGGGACAGAGAGT
ROS1-CD74chr6117700221chr5149782187514YTAVLRGQRCACAGCTGTTCTTCGGGGACAGAGAGT
ROS1-CD74chr6117700221chr5149782187615TAVLRGQRVAGCTGTTCTTCGGGGACAGAGAGTCAC

check button mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs.
Fusion geneHchrHbpTchrTbpStart in +/-13AAEnd in +/-13AAFusionNeoAntigen peptideFusionNEoAntigen RNA sequence
ROS1-CD74chr6117700221chr5149782187015QCIHLYTAVLRGQRVATGTATTCACCTGTACACAGCTGTTCTTCGGGGACAGAGAGTCAC
ROS1-CD74chr6117700221chr5149782187217IHLYTAVLRGQRVTGTCACCTGTACACAGCTGTTCTTCGGGGACAGAGAGTCACTGGAAC

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Information of the samples that have these potential fusion neoantigens of ROS1-CD74

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
LUADROS1-CD74chr6117700221ENST00000368507chr5149782187ENST00000377795TCGA-86-8278-01A

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Potential target of CAR-T therapy development for ROS1-CD74

check button Predicted 3D structure. We used RoseTTAFold.
387_ROS1-CD74_t000_.e2e.pdb


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
ROS1chr6117700221ENST00000368507CD74chr5149782187ENST00000377795
ROS1chr6117700221ENST00000368508CD74chr5149782187ENST00000377795

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Related Drugs to ROS1-CD74

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 ROS1-CD74

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
HgeneROS1C0007131Non-Small Cell Lung Carcinoma4CTD_human
HgeneROS1C0017638Glioma1CTD_human
HgeneROS1C0025202melanoma1CTD_human
HgeneROS1C0152013Adenocarcinoma of lung (disorder)1CGI;CTD_human
HgeneROS1C0259783mixed gliomas1CTD_human
HgeneROS1C0555198Malignant Glioma1CTD_human
TgeneCD74C0006142Malignant neoplasm of breast1CTD_human
TgeneCD74C0007131Non-Small Cell Lung Carcinoma1CTD_human
TgeneCD74C0023893Liver Cirrhosis, Experimental1CTD_human
TgeneCD74C0162557Liver Failure, Acute1CTD_human
TgeneCD74C0678222Breast Carcinoma1CTD_human
TgeneCD74C1257931Mammary Neoplasms, Human1CTD_human
TgeneCD74C1458155Mammary Neoplasms1CTD_human
TgeneCD74C4704874Mammary Carcinoma, Human1CTD_human