The landscape of genetic aberrations in myxofibrosarcoma

Takeuchi, Yasuhide; Yoshida, Kenichi; Halik, Adriane; Kunitz, Annegret; Suzuki, Hiromichi; Kakiuchi, Nobuyuki; Shiozawa, Yusuke; Yokoyama, Akira; Inoue, Yoshikage; Hirano, Toshio; Fujii, Yoichi; Nannya, Yasuhito; Makishima, Hideki; Pfitzner, Berit Maria; Bullinger, Lars; Hirata, Masahiro; Jinnouchi, Keita; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Okamoto, Takeshi; Haga, Hironori; Ogawa, Seishi; Damm, Frédérik

doi:10.1002/ijc.34051

Cited by 21 publications

(19 citation statements)

References 58 publications

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“…6,[15][16][17] MFS is a sarcoma with distinct histopathologic features 18 but only nonspecific genomic findings identified previously, including typically low TMB with alterations in TP53 and genes encoding proteins in the cell cycle. 1,2 Prior methylation array studies have shown that MFS and most UPS cluster together, supporting that they represent a histopathologic spectrum of a single disease. 4 MFS shows the highest AXL mRNA expression level in the TCGA data set compared with normal tissues, other cancer types, and even other sarcoma types.…”

Section: Discussionmentioning

confidence: 98%

“…The tumor shares overlapping genomic features with undifferentiated pleomorphic sarcoma (UPS), including widespread copy number alterations and often low tumor mutational burden (TMB, mutations/Mb) with mutations in TP53 and in genes associated with cell cycle checkpoints (RB1, CDKN2A). [1][2][3] Moreover, methylation array studies have shown that MFS and most cases of UPS cluster similarly, implying that they constitute a morphologic spectrum of a single disease. 4 Although MFS has distinct histopathologic features, no recurrent genetic alterations specific to MFS/UPS have been identified and, as a consequence, there are no effective targeted therapies.…”

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confidence: 99%

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Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma

Williams,

Vegas,

El-Senduny

et al. 2024

American Journal of Surgical Pathology

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Myxofibrosarcoma (MFS) is a common soft tissue sarcoma of the elderly that typically shows low tumor mutational burden, with mutations in TP53 and in genes associated with cell cycle checkpoints (RB1, CDKN2A). Unfortunately, no alterations or markers specific to MFS have been identified and, as a consequence, there are no effective targeted therapies. The receptor tyrosine kinase AXL, which drives cellular proliferation, is targetable by new antibody-based therapeutics. Expression of AXL messenger RNA is elevated in a variety of sarcoma types, with the highest levels reported in MFS, but the pathogenic significance of this finding remains unknown. To assess a role for AXL abnormalities in MFS, we undertook a search for AXL genomic alterations in a comprehensive genomic profiling database of 463,546 unique tumors (including 19,879 sarcomas, of which 315 were MFS) interrogated by targeted next-generation DNA and/or RNA sequencing. Notably, the only genomic alterations recurrent in a specific sarcoma subtype were AXL W451C (n = 8) and AXL W450C (n = 2) mutations. The tumors involved predominantly older adults (age: 44 to 81 [median: 72] y) and histologically showed epithelioid and spindle-shaped cells in a variably myxoid stroma, with 6 cases diagnosed as MFS, 3 as undifferentiated pleomorphic sarcoma (UPS), and 1 as low-grade sarcoma. The AXL W451C mutation was not identified in any non-sarcoma malignancy. A review of publicly available data sets revealed a single AXL W451C-mutant case of UPS that clustered with MFS/UPS by methylation profiling. Functional studies revealed a novel activation mechanism: the W451C mutation causes abnormal unregulated dimerization of the AXL receptor tyrosine kinase through disulfide bond formation between pairs of mutant proteins expressing ectopic cysteine residues. This dimerization triggers AXL autophosphorylation and activation of downstream ERK signaling. We further report sarcomas of diverse histologic subtypes with AXL gene amplifications, with the highest frequency of amplification identified in MFS cases without the W451C mutation. In summary, the activating AXL W451C mutation appears highly specific to MFS, with a novel mechanism to drive unregulated signaling. Moreover, AXL gene amplifications and messenger RNA overexpression are far more frequent in MFS than in other sarcoma subtypes. We conclude that these aberrations in AXL are distinct features of MFS and may aid diagnosis, as well as the selection of available targeted therapies.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma

Williams,

Vegas,

El-Senduny

et al. 2024

American Journal of Surgical Pathology

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“…Available target therapies are hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies, and monoclonal antibodies that provide toxic molecules [ 161 ]. Sometimes, the tumors can express a multitude of genetic aberrations [ 162 ]. Mutations or variants of a single gene may have different consequences, and the response to target therapies may differ depending on the context [ 158 ].…”

Section: Therapeutic Perspectives On Biosensors and Biomarkers In Can...mentioning

confidence: 99%

Biosensing chips for cancer diagnosis and treatment: a new wave towards clinical innovation

Iqbal¹,

Javed

Herrera‐Bravo

et al. 2022

Cancer Cell Int

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Recent technological advances in nanoscience and material designing have led to the development of point-of-care devices for biomolecule sensing and cancer diagnosis. In situ and portable sensing devices for bedside, diagnosis can effectively improve the patient’s clinical outcomes and reduce the mortality rate. Detection of exosomal RNAs by immuno-biochip with increased sensitivity and specificity to diagnose cancer has raised the understanding of the tumor microenvironment and many other technology-based biosensing devices hold great promise for clinical innovations to conquer the unbeatable fort of cancer metastasis. Electrochemical biosensors are the most sensitive category of biomolecule detection sensors with significantly low concentrations down to the atomic level. In this sense, this review addresses the recent advances in cancer detection and diagnosis by developing significant biological sensing devices that are believed to have better sensing potential than existing facilities.

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“…It was found to have prognostic and predictive value for hepatocellular carcinoma together with fourteen others transcription factors (67). Recently, recurrent ZNF780A mutations were reported in myxofibrosarcomas (68). The exact cellular function of ZNF780A and its role in the development and progression of neoplasms are currently unknown.…”

Section: Figure 3 Acgh Showing the Deleted Part Of The P Arm Of Chrom...mentioning

confidence: 99%

NovelMYCBP::EHD2andRUNX1::ZNF780AFusion Genes in T-cell Acute Lymphoblastic Leukemia

Panagopoulos

Andersen

Johannsdottir

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: T-cell acute lymphoblastic leukemia (T-ALL) is a rare malignancy characterized by proliferation of early T-cell precursors that replace normal hematopoietic cells. T-ALL cells carry non-random chromosome aberrations, fusion genes, and gene mutations, often of prognostic significance. We herein report the genetic findings in cells from a T-ALL patient. Materials and Methods:Bone marrow cells from a patient with T-ALL were examined using G-banding, array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization. Results: G-banding revealed del(1)(p34), add(5)(q14), trisomy 8, and monosomy 21 in the leukemic cells. aCGH detected the gross unbalances inferred from the karyotyping results, except that heterozygous loss of chromosome 21 did not include its distal part; 21q22.12-q22.3 was undeleted. In addition, aCGH detected a submicroscopic interstitial 7.56 Mbp deletion in the q arm of chromosome 19 from 19q13.2 to 19q13.33. RNA sequencing detected and RT-PCR/Sanger sequencing confirmed the presence of two novel chimeras, MYCBP::EHD2 and RUNX1::ZNF780A. They were generated from rearrangements involving subbands 1p34.3 (MYCBP), 19q13.2 (ZNF780A), 19q13.33 (EHD2), and 21q22.12 (RUNX1), i.e., at the breakpoints of chromosomal deletions. Conclusion: The leukemic cells showed the heterozygous loss of many genes as well as the generation of MYCBP::EHD2 and RUNX1::ZNF780A chimeras. Because the partner genes in the chimeras were found at the breakpoints of the chromosomal deletions, we believe that both the heterozygous losses and the generation of the two chimeras occurred simultaneously, and that they were pathogenetically important.

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The landscape of genetic aberrations in myxofibrosarcoma

Cited by 21 publications

References 58 publications

Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma

Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma

Biosensing chips for cancer diagnosis and treatment: a new wave towards clinical innovation

NovelMYCBP::EHD2andRUNX1::ZNF780AFusion Genes in T-cell Acute Lymphoblastic Leukemia

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