Research ArticleArticles
Open Access

Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration

IOANNIS PANAGOPOULOS, KRISTIN ANDERSEN, LUDMILA GORUNOVA and INGVILD LOBMAIER
Cancer Genomics & Proteomics May 2024, 21 (3) 252-259; DOI: https://doi.org/10.21873/cgp.20444

Abstract

Background/Aim: The term “calcified chondroid mesenchymal neoplasm” was introduced in 2021 to describe a group of tumors characterized by various morphological features, including the formation of cartilage or chondroid matrix. These tumors frequently carry chimeric genes where the 5′-end partner gene is fibronectin 1 and the 3′-end partner gene codes for receptor tyrosine kinase. Our study explores fusion of the genes platelet-derived growth factor receptor alpha (PDGFRA) and ubiquitin-specific peptidase 8 (USP8) in calcified chondroid mesenchymal neoplasm. Case Report: Genetic investigations were conducted on a tumor located in the leg of a 71-year-old woman. G-banding analysis of short-term cultured tumor cells revealed the karyotype 46,XX,t(4;15)(q12;q21)[6]/46,XX[4]. RNA sequencing detected in-frame PDGFRA::USP8 and USP8::PDGFRA chimeric transcripts, which were validated by RT-PCR/Sanger sequencing. The PDGFRA::USP8 chimeric protein is predicted to have cell membrane location and functions as a chimeric ubiquitinyl hydrolase. The USP8::PDGFRA protein was predicted to be nuclear and function as a positive regulator of cellular metabolic process. Conclusion: We report, for the first time, a calcified chondroid mesenchymal neoplasm carrying a balanced t(4;15)(q12;q21) chromosomal translocation, resulting in the generation of both PDGFRA::USP8 and USP8::PDGFRA chimeras. The PDGFRA::USP8 protein is located on the cell membrane and functions as a chimeric ubiquitinyl hydrolase, activated by PDGFs. Conversely, USP8::PDGFRA is a nuclear protein regulating metabolic processes.

Key Words:

The term “calcified chondroid mesenchymal neoplasm” describes a group of tumors that exhibit a range of morphological features, including the formation of cartilage or chondroid matrix (1).

These tumors frequently carry chimeric genes where the 5′-end partner gene is fibronectin 1 (FN1, located on chromosome band 2q35) and the 3′-end partner gene codes for receptor tyrosine kinase (1). The original study of 12 calcified chondroid mesenchymal neoplasms showed a predilection for the distal extremities and temporomandibular joint, a multinodular architecture with chondroid/cartilaginous matrix, increased cellularity towards the periphery of the nodules, frequent dirty to lacy (chondroblastoma-like or chicken-wire) calcifications, and biphasic tumor cells that were polygonal to stellate in the matrix-rich areas and spindled in the fibrous septa (1). Additional features included osteoclast-like giant cells and, in a subset of cases, areas resembling tenosynovial giant cell tumors. FN1 chimeras with various 3′-end partner genes were found in 10 out of the 12 tumors. However, the most frequent 3′-end partner gene was fibroblast growth factor receptor 2 (FGFR2) from chromosome band 10q26 (FN1::FGFR2 chimera) (1).

Recently, four calcified chondroid mesenchymal neoplasms were reported to carry a fusion of the genes platelet derived growth factor receptor alpha (PDGFRA) from 4q12 and ubiquitin specific peptidase 8 (USP8) from 15q21 (PDGFRA::USP8 chimera) (2). We present cytogenetic and molecular genetic findings of a calcified chondroid mesenchymal neoplasm.

Case Report

Ethics statement. The study was approved by the Regional Ethics Committee. The administrator of the approval application is the leader of the Section for Cancer Cytogenetics Dr. Francesca Micci (Regional komité for medisinsk forskningsetikk Sør-Øst, Norge, http://helseforskning.etikkom.no; 2010/1389/REK sør-øst A). Written informed consent was obtained from the patient. The Ethics Committee’s approval included a review of the consent procedure. All patient information has been de-identified.

Patient. The patient, a 71-year-old woman, has had intermittent pain in her right calf for many years, with resent progression. Radiological examination revealed an elongated, fusiform lesion in the gastrocnemius muscle, subfascial. No apparent enlargement over time. Resected due to pain. On macroscopical examination, the tumor shows areas with calcification. The microscopical examination shows a lobulated mesenchymal neoplasm with a chondroid matrix with calcification and focal cartilage and bone formation (Figure 1).

Figure 1.
Figure 1.

Microscopic examination of the calcified chondroid mesenchymal neoplasm. Hematoxylin and eosin (H&E) stained section showing polygonal to epithelioid cells in a chondrohyaline matrix with areas of fine and coarse calcification. (A) Magnification ×100. (B) Magnification ×200.

G-banding and karyotyping. Fresh tissue from a representative area of the tumor was cytogenetically analyzed as part of our diagnostic routine. The methodology for G-banding and karyotyping has been described previously (3, 4). The samples were disaggre gated mechanically and enzymatically with collagenase II (Worthington, Freehold, NJ, USA). The resulting cells were cultured and harvested using standard techniques. Chromosome preparations were G-banded with Wright’s stain (Sigma-Aldrich, St Louis, MO, USA) and examined. Metaphases were analyzed and karyograms prepared using the CytoVision computer assisted karyotyping system (Leica Biosystems, Newcastle, UK). The karyotype was reported according to the International System for Human Cytogenomic Nomenclature (5).

RNA sequencing. Total RNA was extracted from frozen (-80 °C) tumor tissue adjacent to that used for cytogenetic analysis and histological examination using the miRNeasy Mini Kit and Qiacube (Qiagen, Hilden, Germany). The concentration was measured using a QIAxpert microfluidic UV/VIS spectrophotometer (Qiagen). RNA integrity was assessed with an Agilent 2100 bioanalyzer and DV200 index, which was found to be 70% (6). Total RNA (200 ng) was sent to the Genomics Core Facility at the Norwegian Radium Hospital, Oslo University Hospital, for high-throughput paired-end RNA-sequencing. FusionCatcher software was used to detect potential fusion transcripts (7, 8).

Confirmation of the fusion transcripts. The presence of fusion transcripts was confirmed by reverse transcription (RT) polymerase chain reaction (PCR) and Sanger sequencing. The primers used for RT-PCR and Sanger sequencing are listed in Table I. The methodology used in the present study has been described in detail in many of our previous publications (9-12). In brief, 200 ng of total RNA was reverse-transcribed in a 20 μl reaction volume using the iScript Advanced cDNA Synthesis Kit for RT-qPCR according to the manufacturer’s instructions (Bio-Rad, Hercules, CA, USA). cDNA, corresponding to 20 ng total RNA, was used as a template in subsequent PCR assays. PCR amplifications were performed using the primer combinations PDGFRA-3033F1/USP8-1027R1 and USP8-616F1/PDGFRA-3443R1 (Table I). The quality of cDNA synthesis was assessed by amplification of a cDNA fragment from the ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) gene using the primer combination ABL1-91F1/ABL1-404R1 (13). Three μl of the PCR products were stained with GelRed (Biotium, Hayward, CA, USA), analyzed by electrophoresis on 1.5 % agarose gel, and photographed. The remaining PCR products were purified using the MinElute PCR Purification Kit (Qiagen) and sequenced using the BigDye Direct Cycle Sequencing Kit following the manufacturer’s recommendations (Thermo Fisher Scientific, Waltham, MA, USA). The primer combinations were M13For-PDGFRA-3075F1/M13Rev-USP8-984R1 and M13For-USP8-781F1/M13Rev-PDGFRA-3393R1 (Table I).

View this table:
Table I.

Designation, sequence (5′->3′), and position in reference sequences of the forward (F1) and reverse (R1) primers of the platelet derived growth factor receptor alpha (PDGFRA) and the ubiquitin specific peptidase 8 (USP8) genes.

Sequencing was performed using an Applied Biosystems SeqStudio Genetic Analyzer system (Thermo Fisher Scientific). The Basic Local Alignment Search Tool (BLAST) was used to compare the sequences obtained by Sanger sequencing with the National Center for Biotechnology Information (NCBI) reference sequences (14). The reference sequences were NM_006206.6 for PDGFRA transcript variant 1 and NM_005154.5 for USP8 transcript variant 1. In addition, the BLAST-like alignment tool (BLAT) and the human genome browser at University of California, Santa Cruz (UCSC) were used to map the sequences obtained by Sanger sequencing, on the Human GRCh37/hg19 assembly (15, 16).

For the prediction of subcellular localization of the proteins BUSCA and DeepLoc algorithms were used (17, 18). To predict the function of proteins the recently described deep neural network ProteInfer was used (19). For the visualization of the chimeric protein the Protter program was used (20).

Results

G-banding analysis yielded a karyotype with a single chromosome abnormality: 46,XX,t(4;15)(q12;q21)[6]/46, XX[4] (Figure 2A).

Figure 2.
Figure 2.

Genetic examination of the calcified chondroid mesenchymal neoplasm. (A) Partial karyogram showing the der(4)t(4;15)(q12;q21) and der(15)t(4;15)(q12;q21) together with the corresponding normal chromosome homologs. Breakpoint positions are indicated by arrows. (B) Gel electrophoresis showing the amplified ABL1 (lane 1), PDGFRA::USP8 (lane 2) and USP8::PDGFRA (lane 3) cDNA fragments using the primer combinations ABL1-91F1/ABL1-404R1, PDGFRA-3033F1/USP8-1027R1, and USP8-616F1/PDGFRA-3443R1, respectively. M: GeneRuler 1kb Plus DNA ladder (Thermo Fisher Scientific). (C) Partial sequence chromatogram showing the junction position in the PDGFRA::USP8 cDNA amplified fragment. (D) Partial sequence chromatogram showing the junction position in the USP8::PDGFRA cDNA amplified fragment. The exon numbers are based on the sequences with accession numbers NM_006206.6 for PDGFRA and NM_005154.5 for USP8. (E). Illustration showing the coding protein PDGFRA. SP: Signal peptide; IG1: Ig_3 immunoglobulin domain; IG2: immunoglobulin-like domain of platelet-derived growth factor receptors (PDGFR), alpha and beta, member of the I-set of IgSF domains; IG3: fourth immunoglobulin-like domain of PDGFR; TMR: transmembrane region; PTK-CD: catalytic domain of the protein tyrosine kinase. (F) Illustration showing the coding protein USP8. USP8-dimer: USP8 dimerization domain; Rhodanese: Rhodanese-like domain; tolA_full: TolA protein; UCH: ubiquitin carboxyl-terminal hydrolase; FP1: fusionpoint reported by Fisher et al. (2) in calcified mesenchymal neoplasm with PDGFRA::USP8; FP2: fusionpoint reported in the present study in a calcified mesenchymal neoplasm with PDGFRA::USP8; FP3: breakpoint reported in B-cell lineage acute lymphoblastic leukemia carrying KMT2A::USP8 chimera which was generated by chromosomal translocation t(11;15)(q23;q21) (50). The parts of the PDGFRA and USP proteins in yellow compose the chimeric PDGFRA::USP8 protein while the parts in cyan compose the chimeric USP8::PDGFRA protein.

Using FusionCatcher software with fastq files from RNA sequencing, both PDGFRA-USP8 and USP8-PDGFRA chimeric transcript sequences were detected, which corresponded to t(4;15)(q12;q21) (Table II). RT-PCR with the primer combinations PDGFRA-3033F1/USP8-1027R1 and USP8-616F1/PDGFRA-3443R1 amplified 414 bp and 455 bp long cDNA fragments, respectively (Figure 2B). Further sequencing of the cDNA-amplified fragments verified the above-mentioned PDGFRA::USP8 and USP8::PDGFRA chimeric transcripts (Table II and Figure 2C and D). In PDGFRA::USP8 chimeric transcript, exon 22 of PDGFRA fused to exon 8 of USP8 (Figure 2C), whereas in USP8::PDGFRA chimeric transcript exon 7 of USP8 fused to exon 23 of PDGFRA (Figure 2D).

View this table:
Table II.

The PDGFRA::USP8 and USP8::PDGFRA fusion transcripts detected in calcified chondroid mesenchymal neoplasm carrying a t(4;15)(q12;q21) chromosome translocation after analysis of RNA sequencing data with FusionCatcher.

Discussion

Herein, we report a novel t(4;15)(q12;q21) chromosomal translocation as the only cytogenetic aberration in a calcified chondroid mesenchymal neoplasm. The translocation rearranged PDGFRA on chromosome band 4q12 and USP8 on 15q21 and generated PDGFRA::USP8 and USP8::PDGFRA chimeras (Figure 2). Because both PDGFRA and USP8 are transcribed from the centromere to the telomere, the chimeric PDGFRA::USP8 gene is predicted to be on der(4)t(4;15) (q12;q21) whereas USP8::PDGFRA is predicted to be on der(15)t(4;15)(q12;q21). Because in PDGFRA-USP8 chimeric transcript exon 22 of PDGFRA fused to exon 8 of USP8 whereas in USP8::PDGFRA chimeric transcript exon 7 of USP8 fused to exon 23 of PDGFRA the genomic breakpoints are predicted to occur in intron 22 of PDGFRA and intron 7 of USP8. Chimeric PDGFRA::USP8 transcripts have been reported recently in four cases of calcified chondroid mesenchymal neoplasm (2) and in a sarcoma (21) which is registered in cBioPortal database (22) as retroperitoneal undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma/high-grade spindle cell sarcoma (https://www.cbioportal.org/patient?sampleId=TCGA-Z4-AAPG-01&studyId=sarc_tcga_pan_can_atlas_2018). In all the above-mentioned tumors, exon 22 of PDGFRA fused to exon 5 of USP8 (PDGFRA::USP8 chimeric transcript) (2, 21).

The PDGFRA gene codes for a cell surface receptor (Figure 2E), belonging to the receptor tyrosine kinase family, that plays a crucial role in various cellular processes, including cell growth, proliferation, and differentiation (23-26). PDGFRA is activated by binding to its specific ligands, platelet-derived growth factors (PDGFs) (27). Upon ligand binding, the receptor undergoes autophosphorylation, initiating downstream signaling cascades that regulate diverse cellular functions (23-26). Aberrant PDGFRA signaling has been implicated in numerous pathological conditions, including cancer, cardiac fibrosis, and diabetes 2 (23, 26, 28-30). Mutations, overexpression, and fusion genes of PDGFRA have been associated with the development and progression of certain cancers, such as gastrointestinal stromal tumors (31-33), brain tumors (34-36), and hematological neoplasms (37, 38), making it a potential therapeutic target (24, 25, 33, 39-41).

The USP8 gene codes for a protein (officially named ubiquitin carboxyl-terminal hydrolase 8) that belongs to the ubiquitin-specific processing protease family of proteins (Figure 2F). USP8 is a deubiquitinase enzyme that plays a key role in the regulation of several cellular processes by cleaving ubiquitin molecules from substrate proteins (42, 43). USP8 is particularly notable for its involvement in endosomal trafficking and receptor signaling (42, 43). It regulates the ubiquitination status of several important membrane proteins, including receptor tyrosine kinases such as epidermal growth factor receptor (EGFR). USP8 deubiquitinates these receptors, prevents their degradation, and promotes their recycling back to the cell surface. This activity contributes to the fine-tuning of signaling cascades involved in cell growth, proliferation, and differentiation (42-45). Somatic mutations of the USP8 gene have been found in adenomas causing Cushing’s disease (46-48), and abnormal expression of USP8 has been found in various neoplasms (43, 49, 50). The Mitelman database of chromosome aberrations and gene fusions in cancer has documented 14 chimeric genes involving USP8, including a fusion between USP8 and lysine methyltransferase 2A (KMT2A) in B-cell lineage acute lymphoplastic leukemia. The KMT2A::USP8 chimera was generated by chromosomal translocation t(11;15)(q23;q21) (51, 52). The genomic breakpoints occurred within introns 20 and 12 of KMT2A and USP8 (NM_005154), respectively. This resulted in an in-frame KMT2A::USP8 chimeric transcript comprising exons 1-20 of KMT2A and exons 13-20 of USP8 (51).

Based on the reference sequences NM_006206.6/NP_006197.1 for PDGFRA and NM_005154.5/NP_005145.3 for USP8, the chimeric PDGFRA::USP8 transcript was predicted to code for a 1930-amino acid protein. This protein comprises the first 1040 amino acids of PDGFRA (amino acid 1-1040 in NP_006197.1), an arginine generated at the fusion point, and the last 889 amino acids of USP8 (amino acid 230-1118 in NP_005145.3) (Figure 2E and F). Therefore, the PDGFRA::USP8 protein contains all regions of PDGFRA, that is, the signal peptide, immunoglobulin domains, transmembrane region, and catalytic domain of the protein tyrosine kinase (Figure 2E). Additionally, it includes the USP8 regions rhodanase, tolA_full, and ubiquitin carboxyl-terminal hydrolase (Figure 2F). Based on BUSCA, DeepLoc, and ProteInfer, the PDGFRA::USP8 protein is predicted to have a cell membrane location and function as a chimeric ubiquitinyl hydrolase, which is activated by PDGFs (Figure 3). Using a monoclonal antibody corresponding to the PDGFRA extracellular domain, Fisher and coworkers (2) detected a strong distinct membranous staining of PDGFRA on the neoplastic chondrocytic cells. This result supports the predicted subcellular location of PDGFRA::USP8 protein, which we describe in the present work.

Figure 3.
Figure 3.

Illustration showing the cell membrane location of the chimeric PDGFRA::USP8 protein. The illustration is based on the reference sequences NM_006206.6/NP_006197.1 for PDGFRA and NM_005154.5/NP_005145.3 for USP8. SP: Signal peptide; IG1: Ig_3 immunoglobulin domain; IG2: immunoglobulin-like domain of platelet-derived growth factor receptors (PDGFR), alpha and beta, member of the I-set of IgSF domains; IG3: fourth immunoglobulin-like domain of PDGFR; TMR: transmembrane region; Rhod: Rhodanese-like domain; tolA_full: TolA protein. Illustration was made with the Protter program (20).

The anticipated product of the USP8::PDGFRA transcript is a 277-amino acid protein composed of the first 229 amino acids of USP8 (1-229 of NP_005145.3), which contains the USP8 dimerization domain, and the last 47 amino acids of the PDGFRA protein (amino acids1042-1089 of NP_006197.1) (Figure 2E and F). The predicted subcellular localization of the USP8::PDGFRA protein is in the nucleus and its function is to positively regulate cellular metabolic processes.

In conclusion, we report, for the first time, a calcified chondroid mesenchymal neoplasm carrying a balanced t(4;15)(q12;q21) chromosomal translocation, resulting in the generation of PDGFRA::USP8 and USP8::PDGFRA chimeras. The PDGFRA::USP8 protein is predicted to be located on the cell membrane and function as a chimeric ubiquitinyl hydrolase, activated by PDGFs. Conversely, USP8::PDGFRA is predicted to be a nuclear protein that positively regulates cellular metabolic processes.

Acknowledgements

We thank the leader of the Section for Cancer Cytogenetics Dr. Francesca Micci for general administrative support. This project was financially supported by internal funding program of the Institute for Cancer Genetics and Informatics.

Footnotes

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest regarding this study.

  • Authors’ Contributions

    IP designed and supervised the research, performed molecular genetic experiments and bioinformatic analysis, and wrote the article. KA performed molecular genetic experiments. LG performed cytogenetic analysis. IL performed pathological examination. All Authors have read and approved the final manuscript.

  • Received January 20, 2024.
  • Revision received March 14, 2024.
  • Accepted March 19, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Liu YJ,
    2. Wang W,
    3. Yeh J,
    4. Wu Y,
    5. Mantilla JG,
    6. Fletcher CD,
    7. Ricciotti RW,
    8. Chen EY
    : Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including FGFR2, FGFR1, MERTK, NTRK1, and TEK: a molecular and clinicopathologic analysis. Mod Pathol 34(7): 1373-1383, 2021. DOI: 10.1038/s41379-021-00786-x
    OpenUrlCrossRef
  2. ↵
    1. Fisher Y,
    2. Lacambra MD,
    3. Almohsen SS,
    4. Chow C,
    5. Hornick JL,
    6. To KF,
    7. Dickson BC
    : Expanding the spectrum of tyrosine kinase fusions in calcified chondroid mesenchymal neoplasms: Identification of a novel PDGFRA::USP8 gene fusion. Genes Chromosomes Cancer 63(1): e23197, 2024. DOI: 10.1002/gcc.23197
    OpenUrlCrossRef
  3. ↵
    1. Polito P,
    2. Dal Cin P,
    3. Debiec-Rychter M,
    4. Hagemeijer A
    : Human solid tumors: cytogenetic techniques. Methods Mol Biol 220: 135-150, 2003. DOI: 10.1385/1-59259-363-1:135
    OpenUrlCrossRefPubMed
  4. ↵
    1. Lukeis R,
    2. Suter M
    : Cytogenetics of solid tumours. Methods Mol Biol 730: 173-187, 2011. DOI: 10.1007/978-1-61779-074-4_13
    OpenUrlCrossRefPubMed
  5. ↵
    1. McGowan-Jordan J,
    2. Hastings RJ,
    3. Moore S
    : ISCN 2020: An International system for human cytogenomic nomenclature. Basel, Switzerland, Karger, pp. 164, 2020.
  6. ↵
    1. Matsubara T,
    2. Soh J,
    3. Morita M,
    4. Uwabo T,
    5. Tomida S,
    6. Fujiwara T,
    7. Kanazawa S,
    8. Toyooka S,
    9. Hirasawa A
    : DV200 index for assessing RNA integrity in next-generation sequencing. Biomed Res Int 2020: 9349132, 2020. DOI: 10.1155/2020/9349132
    OpenUrlCrossRef
  7. ↵
    1. Kangaspeska S,
    2. Hultsch S,
    3. Edgren H,
    4. Nicorici D,
    5. Murumägi A,
    6. Kallioniemi O
    : Reanalysis of RNA-sequencing data reveals several additional fusion genes with multiple isoforms. PLoS One 7(10): e48745, 2012. DOI: 10.1371/journal.pone.0048745
    OpenUrlCrossRefPubMed
  8. ↵
    1. Nicorici D,
    2. Satalan H,
    3. Edgren H,
    4. Kangaspeska S,
    5. Murumagi A,
    6. Kallioniemi O,
    7. Virtanen S,
    8. Kikku O
    : FusionCatcher – a tool for finding somatic fusion genes in paired-end RNA-sequencing data. bioRxiv, 2014. DOI: 10.1101/011650
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Panagopoulos I,
    2. Gorunova L,
    3. Andersen K,
    4. Lund-Iversen M,
    5. Lobmaier I,
    6. Micci F,
    7. Heim S
    : NDRG1-PLAG1 and TRPS1-PLAG1 fusion genes in chondroid syringoma. Cancer Genomics Proteomics 17(3): 237-248, 2020. DOI: 10.21873/cgp.20184
    OpenUrlAbstract/FREE Full Text
    1. Panagopoulos I,
    2. Andersen K,
    3. Gorunova L,
    4. Eilert-Olsen M,
    5. Lund-Iversen M,
    6. Wessel-Aas T,
    7. Lloret I,
    8. Micci F,
    9. Heim S
    : Presence of a t(12;18)(q14;q21) chromosome translocation and fusion of the genes for high-mobility group AT-Hook 2 (HMGA2) and WNT inhibitory factor 1 (WIF1) in infrapatellar fat pad cells from a patient with Hoffa’s disease. Cancer Genomics Proteomics 19(5): 584-590, 2022. DOI: 10.21873/cgp.20343
    OpenUrlAbstract/FREE Full Text
    1. Panagopoulos I,
    2. Gorunova L,
    3. Andersen K,
    4. Lobmaier I,
    5. Micci F,
    6. Heim S
    : Fusion of high mobility group AT-hook 2 gene (HMGA2) with the chromosome 12 open reading frame 42 gene (C12orf42) in an aggressive angiomyxoma with del(12)(q14q23) as the sole cytogenetic anomaly. Cancer Genomics Proteomics 19(5): 576-583, 2022. DOI: 10.21873/cgp.20342
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Panagopoulos I,
    2. Andersen K,
    3. Brunetti M,
    4. Gorunova L,
    5. Lund-Iversen M,
    6. Micci F,
    7. Heim S
    : Fusion of the high-mobility group AT-Hook 2 (HMGA2) and the Gelsolin (GSN) genes in lipomas with t(9;12)(q33;q14) chromosomal translocation. In Vivo 37(2): 524-530, 2023. DOI: 10.21873/invivo.13110
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Torkildsen S,
    2. Brunetti M,
    3. Gorunova L,
    4. Spetalen S,
    5. Beiske K,
    6. Heim S,
    7. Panagopoulos I
    : Rearrangement of the chromatin organizer special AT-rich binding protein 1 gene, SATB1, resulting from a t(3;5)(p24;q14) chromosomal translocation in acute myeloid leukemia. Anticancer Res 37(2): 693-698, 2017. DOI: 10.21873/anticanres.11365
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Altschul SF,
    2. Gish W,
    3. Miller W,
    4. Myers EW,
    5. Lipman DJ
    : Basic local alignment search tool. J Mol Biol 215(3): 403-410, 1990. DOI: 10.1016/S0022-2836(05)80360-2
    OpenUrlCrossRefPubMed
  15. ↵
    1. Kent WJ
    : BLAT—the BLAST-like alignment tool. Genome Res 12(4): 656-664, 2002. DOI: 10.1101/gr.229202
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Kent WJ,
    2. Sugnet CW,
    3. Furey TS,
    4. Roskin KM,
    5. Pringle TH,
    6. Zahler AM,
    7. Haussler D
    : The human genome browser at UCSC. Genome Res 12(6): 996-1006, 2002. DOI: 10.1101/gr.229102
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Almagro Armenteros JJ,
    2. Sønderby CK,
    3. Sønderby SK,
    4. Nielsen H,
    5. Winther O
    : DeepLoc: prediction of protein subcellular localization using deep learning. Bioinformatics 33(21): 3387-3395, 2017. DOI: 10.1093/bioinformatics/btx431
    OpenUrlCrossRefPubMed
  18. ↵
    1. Savojardo C,
    2. Martelli PL,
    3. Fariselli P,
    4. Profiti G,
    5. Casadio R
    : BUSCA: an integrative web server to predict subcellular localization of proteins. Nucleic Acids Res 46(W1): W459-W466, 2018. DOI: 10.1093/nar/gky320
    OpenUrlCrossRefPubMed
  19. ↵
    1. Sanderson T,
    2. Bileschi ML,
    3. Belanger D,
    4. Colwell LJ
    : ProteInfer, deep neural networks for protein functional inference. Elife 12: e80942, 2023. DOI: 10.7554/eLife.80942
    OpenUrlCrossRef
  20. ↵
    1. Omasits U,
    2. Ahrens CH,
    3. Müller S,
    4. Wollscheid B
    : Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics 30(6): 884-886, 2014. DOI: 10.1093/bioinformatics/btt607
    OpenUrlCrossRefPubMed
  21. ↵
    1. Hu X,
    2. Wang Q,
    3. Tang M,
    4. Barthel F,
    5. Amin S,
    6. Yoshihara K,
    7. Lang FM,
    8. Martinez-Ledesma E,
    9. Lee SH,
    10. Zheng S,
    11. Verhaak RGW
    : TumorFusions: an integrative resource for cancer-associated transcript fusions. Nucleic Acids Res 46(D1): D1144-D1149, 2018. DOI: 10.1093/nar/gkx1018
    OpenUrlCrossRef
  22. ↵
    1. Cerami E,
    2. Gao J,
    3. Dogrusoz U,
    4. Gross BE,
    5. Sumer SO,
    6. Aksoy BA,
    7. Jacobsen A,
    8. Byrne CJ,
    9. Heuer ML,
    10. Larsson E,
    11. Antipin Y,
    12. Reva B,
    13. Goldberg AP,
    14. Sander C,
    15. Schultz N
    : The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5): 401-404, 2012. DOI: 10.1158/2159-8290.CD-12-0095
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Andrae J,
    2. Gallini R,
    3. Betsholtz C
    : Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10): 1276-1312, 2008. DOI: 10.1101/gad.1653708
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Heldin CH
    : Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal 11: 97, 2013. DOI: 10.1186/1478-811X-11-97
    OpenUrlCrossRefPubMed
  25. ↵
    1. Heldin C
    : Targeting the PDGF signaling pathway in the treatment of non-malignant diseases. J Neuroimmune Pharmacol 9(2): 69-79, 2014. DOI: 10.1007/s11481-013-9484-2
    OpenUrlCrossRefPubMed
  26. ↵
    1. Heldin CH,
    2. Lennartsson J,
    3. Westermark B
    : Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J Intern Med 283(1): 16-44, 2018. DOI: 10.1111/joim.12690
    OpenUrlCrossRefPubMed
  27. ↵
    1. Kazlauskas A
    : PDGFs and their receptors. Gene 614: 1-7, 2017. DOI: 10.1016/j.gene.2017.03.003
    OpenUrlCrossRefPubMed
  28. ↵
    1. Frangogiannis NG
    : Cardiac fibrosis. Cardiovasc Res 117(6): 1450-1488, 2021. DOI: 10.1093/cvr/cvaa324
    OpenUrlCrossRefPubMed
    1. Guérit E,
    2. Arts F,
    3. Dachy G,
    4. Boulouadnine B,
    5. Demoulin JB
    : PDGF receptor mutations in human diseases. Cell Mol Life Sci 78(8): 3867-3881, 2021. DOI: 10.1007/s00018-020-03753-y
    OpenUrlCrossRef
  30. ↵
    1. Cao Z,
    2. Liu Y,
    3. Wang Y,
    4. Leng P
    : Research progress on the role of PDGF/PDGFR in type 2 diabetes. Biomed Pharmacother 164: 114983, 2023. DOI: 10.1016/j.biopha.2023.114983
    OpenUrlCrossRef
  31. ↵
    1. Corless CL,
    2. Schroeder A,
    3. Griffith D,
    4. Town A,
    5. McGreevey L,
    6. Harrell P,
    7. Shiraga S,
    8. Bainbridge T,
    9. Morich J,
    10. Heinrich MC
    : PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23): 5357-5364, 2005. DOI: 10.1200/jco.2005.14.068
    OpenUrlAbstract/FREE Full Text
    1. Qian H,
    2. Appiah-Kubi K,
    3. Wang Y,
    4. Wu M,
    5. Tao Y,
    6. Wu Y,
    7. Chen Y
    : The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 127: 15-28, 2018. DOI: 10.1016/j.critrevonc.2018.05.004
    OpenUrlCrossRef
  33. ↵
    1. Sun Y,
    2. Yue L,
    3. Xu P,
    4. Hu W
    : An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol 12: 927587, 2022. DOI: 10.3389/fonc.2022.927587
    OpenUrlCrossRef
  34. ↵
    1. Ozawa T,
    2. Brennan CW,
    3. Wang L,
    4. Squatrito M,
    5. Sasayama T,
    6. Nakada M,
    7. Huse JT,
    8. Pedraza A,
    9. Utsuki S,
    10. Yasui Y,
    11. Tandon A,
    12. Fomchenko EI,
    13. Oka H,
    14. Levine RL,
    15. Fujii K,
    16. Ladanyi M,
    17. Holland EC
    : PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24(19): 2205-2218, 2010. DOI: 10.1101/gad.1972310
    OpenUrlAbstract/FREE Full Text
    1. Alentorn A,
    2. Marie Y,
    3. Carpentier C,
    4. Boisselier B,
    5. Giry M,
    6. Labussière M,
    7. Mokhtari K,
    8. Hoang-Xuan K,
    9. Sanson M,
    10. Delattre JY,
    11. Idbaih A
    : Prevalence, clinico-pathological value, and co-occurrence of PDGFRA abnormalities in diffuse gliomas. Neuro Oncol 14(11): 1393-1403, 2012. DOI: 10.1093/neuonc/nos217
    OpenUrlCrossRefPubMed
  36. ↵
    1. Vuong HG,
    2. Le HT,
    3. Dunn IF
    : The prognostic significance of further genotyping H3G34 diffuse hemispheric gliomas. Cancer 128(10): 1907-1912, 2022. DOI: 10.1002/cncr.34156
    OpenUrlCrossRef
  37. ↵
    1. Appiah-Kubi K,
    2. Lan T,
    3. Wang Y,
    4. Qian H,
    5. Wu M,
    6. Yao X,
    7. Wu Y,
    8. Chen Y
    : Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies. Crit Rev Oncol Hematol 109: 20-34, 2017. DOI: 10.1016/j.critrevonc.2016.11.008
    OpenUrlCrossRef
  38. ↵
    1. Pozdnyakova O,
    2. Orazi A,
    3. Kelemen K,
    4. King R,
    5. Reichard KK,
    6. Craig FE,
    7. Quintanilla-Martinez L,
    8. Rimsza L,
    9. George TI,
    10. Horny H,
    11. Wang SA
    : Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. Am J Clin Pathol 155(2): 160-178, 2021. DOI: 10.1093/ajcp/aqaa208
    OpenUrlCrossRef
  39. ↵
    1. Papadopoulos N,
    2. Lennartsson J
    : The PDGF/PDGFR pathway as a drug target. Mol Aspects Med 62: 75-88, 2018. DOI: 10.1016/j.mam.2017.11.007
    OpenUrlCrossRef
    1. Zou X,
    2. Tang XY,
    3. Qu ZY,
    4. Sun ZW,
    5. Ji CF,
    6. Li YJ,
    7. Guo SD
    : Targeting the PDGF/PDGFR signaling pathway for cancer therapy: A review. Int J Biol Macromol 202: 539-557, 2022. DOI: 10.1016/j.ijbiomac.2022.01.113
    OpenUrlCrossRefPubMed
  41. ↵
    1. Pandey P,
    2. Khan F,
    3. Upadhyay TK,
    4. Seungjoon M,
    5. Park MN,
    6. Kim B
    : New insights about the PDGF/PDGFR signaling pathway as a promising target to develop cancer therapeutic strategies. Biomed Pharmacother 161: 114491, 2023. DOI: 10.1016/j.biopha.2023.114491
    OpenUrlCrossRef
  42. ↵
    1. Dufner A,
    2. Knobeloch KP
    : Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions. Biochem Soc Trans 47(6): 1867-1879, 2019. DOI: 10.1042/BST20190527
    OpenUrlCrossRef
  43. ↵
    1. Islam MT,
    2. Chen F,
    3. Chen H
    : The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics. Arch Biochem Biophys 701: 108811, 2021. DOI: 10.1016/j.abb.2021.108811
    OpenUrlCrossRef
    1. Berlin I,
    2. Higginbotham KM,
    3. Dise RS,
    4. Sierra MI,
    5. Nash PD
    : The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor 4 at the sorting endosome. J Biol Chem 285(48): 37895-37908, 2010. DOI: 10.1074/jbc.M110.129411
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Berlin I,
    2. Schwartz H,
    3. Nash PD
    : Regulation of epidermal growth factor receptor ubiquitination and trafficking by the USP8·STAM complex. J Biol Chem 285(45): 34909-34921, 2010. DOI: 10.1074/jbc.M109.016287
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Perez-Rivas LG,
    2. Theodoropoulou M,
    3. Ferraù F,
    4. Nusser C,
    5. Kawaguchi K,
    6. Stratakis CA,
    7. Faucz FR,
    8. Wildemberg LE,
    9. Assié G,
    10. Beschorner R,
    11. Dimopoulou C,
    12. Buchfelder M,
    13. Popovic V,
    14. Berr CM,
    15. Tóth M,
    16. Ardisasmita AI,
    17. Honegger J,
    18. Bertherat J,
    19. Gadelha MR,
    20. Beuschlein F,
    21. Stalla G,
    22. Komada M,
    23. Korbonits M,
    24. Reincke M
    : The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s disease. J Clin Endocrinol Metab 100(7): E997-1004, 2015. DOI: 10.1210/jc.2015-1453
    OpenUrlCrossRefPubMed
    1. Locantore P,
    2. Paragliola RM,
    3. Cera G,
    4. Novizio R,
    5. Maggio E,
    6. Ramunno V,
    7. Corsello A,
    8. Corsello SM
    : Genetic basis of ACTH-secreting adenomas. Int J Mol Sci 23(12): 6824, 2022. DOI: 10.3390/ijms23126824
    OpenUrlCrossRef
  48. ↵
    1. Theodoropoulou M,
    2. Reincke M
    : Genetics of Cushing’s disease: from the lab to clinical practice. Pituitary 25(5): 689-692, 2022. DOI: 10.1007/s11102-022-01253-9
    OpenUrlCrossRef
  49. ↵
    1. Jing X,
    2. Chen Y,
    3. Chen Y,
    4. Shi G,
    5. Lv S,
    6. Cheng N,
    7. Feng C,
    8. Xin Z,
    9. Zhang L,
    10. Wu J
    : Down-regulation of USP8 inhibits cholangiocarcinoma cell proliferation and invasion. Cancer Manag Res 12: 2185-2194, 2020. DOI: 10.2147/CMAR.S234586
    OpenUrlCrossRef
  50. ↵
    1. Rong Z,
    2. Zhu Z,
    3. Cai S,
    4. Zhang B
    : Knockdown of USP8 inhibits the growth of lung cancer cells. Cancer Manag Res 12: 12415-12422, 2020. DOI: 10.2147/IJN.S259191
    OpenUrlCrossRef
  51. ↵
    1. Blackburn PR,
    2. Smadbeck JB,
    3. Znoyko I,
    4. Webley MR,
    5. Pitel BA,
    6. Vasmatzis G,
    7. Xu X,
    8. Greipp PT,
    9. Hoppman NL,
    10. Ketterling RP,
    11. Baughn LB,
    12. Lindsey KG,
    13. Schandl CA,
    14. Wolff DJ,
    15. Peterson JF
    : Cryptic and atypical KMT2A-USP2 and KMT2A-USP8 rearrangements identified by mate pair sequencing in infant and childhood leukemia. Genes Chromosomes Cancer 59(7): 422-427, 2020. DOI: 10.1002/gcc.22842
    OpenUrlCrossRef
  52. ↵
    1. Mitelman F,
    2. Johansson B,
    3. Mertens F
    : Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. Available at: https://mitelmandatabase.isb-cgc.org/ [Last updated on January 16, 2024]
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Fusion of Platelet Derived Growth Factor Receptor Alpha (PDGFRA) With Ubiquitin Specific Peptidase 8 (USP8) in a Calcified Chondroid Mesenchymal Neoplasm Harboring t(4;15)(q12;q21) as a Sole Aberration
IOANNIS PANAGOPOULOS, KRISTIN ANDERSEN, LUDMILA GORUNOVA, INGVILD LOBMAIER
Cancer Genomics & Proteomics May 2024, 21 (3) 252-259; DOI: 10.21873/cgp.20444
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords