Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis

Translocations involving FN1 have been described in a variety of neoplasms, which share the presence of cartilage matrix and a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical and pathologic features of 9 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel, including FN1, FGFR1 and FGFR2. All 9 cases were positive for a gene fusion, including two novel fusions, FN1-MERTK and FN1-TEK, each in one case, recurrent FN1-FGFR2 in 5 cases, FN1-FGFR1 without the Ig3 domain in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5′ partner gene FN1 ranged from exons 11-48, retaining the domains of signal peptide, FN1, FN2, and/or FN3, while the 3 ′ partner genes retained the trans-membrane domain, tyrosine kinase domains and /or Ig domain. The tumors with FN1-FGFR1, FN1-FGFR2 and FN1-MERTK fusions are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification. These features resemble those as described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include calcium pyrophosphate dehydrate deposition and features resembling tenosynovial giant cell tumor. Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe novel findings that expand the morphologic spectrum of these neoplasms and have therefore labeled them as calcified chondroid mesenchymal neoplasms. These neoplasms represent a distinct pathologic entity given the presence of recurrent FN1-receptor tyrosine kinase fusions.

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Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including FGFR2, FGFR1, MERTK, NTRK1, and TEK: a molecular and clinicopathologic analysis

Modern Pathology ◽

10.1038/s41379-021-00786-x ◽

2021 ◽

Author(s):

Yajuan J. Liu ◽

Wenjing Wang ◽

Jeffrey Yeh ◽

Yu Wu ◽

Jose G. Mantilla ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Gene Fusions ◽

Kinase Gene ◽

Mesenchymal Neoplasms ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene

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Abstract 894: Targeting ROS1 receptor tyrosine kinase gene fusions in non-small cell lung cancer

10.1158/1538-7445.am2012-894 ◽

2012 ◽

Author(s):

Kurtis D. Davies ◽

Anh T. Le ◽

Margaret C. Skokan ◽

Mariana F. Theodoro ◽

Marileila Varella-Garcia ◽

...

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Receptor Tyrosine Kinase ◽

Small Cell ◽

Gene Fusions ◽

Small Cell Lung ◽

Kinase Gene ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene

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Receptor Tyrosine Kinase Gene

10.32388/um4tbt ◽

2020 ◽

Author(s):

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Kinase Gene ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene

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HGG-34. DETECTION OF ONCOGENIC FUSION EVENTS IN SUPRATENTORIAL GLIOBLASTOMAS OF YOUNG CHILDREN

Neuro-Oncology ◽

10.1093/neuonc/noaa222.315 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii349-iii350

Author(s):

Torsten Pietsch ◽

Christian Vokuhl ◽

Gerrit H Gielen ◽

Andre O von Bueren ◽

Everlyn Dörner ◽

...

Keyword(s):

Tyrosine Kinase ◽

Rna Sequencing ◽

First Year ◽

Gene Fusions ◽

Older Children ◽

Kinase Gene ◽

Dna And Rna ◽

Infancy And Early Childhood ◽

Stable Genome ◽

First Year Of Life

Abstract INTRODUCTION Glioblastoma in infancy and early childhood is characterized by a more favorable outcome compared to older children, a stable genome, and the occurrence of tyrosine kinase gene fusions that may represent therapeutic targets. METHODS 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET, Molecular Inversion Probe (MIP) methodology, and targeted RNA sequencing. RESULTS 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different fusion partners; all occurred in the first year of life (18/37 cases, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two novel fusions. The different methods led to comparable results; targeted RNA sequencing was not successful in a fraction of cases. Break-apart FISH led to reliable results on the next day, MIP technology represented the most sensitive method for analysis of FFPE samples. CONCLUSIONS Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of children younger than four years; the most frequent were ALK fusions occurring in infant GBM. DNA based MIP technology represented the most robust and sensitive assay.

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Distinct Mutations in the Receptor Tyrosine Kinase Gene ROR2 Cause Brachydactyly Type B

The American Journal of Human Genetics ◽

10.1086/303084 ◽

2000 ◽

Vol 67 (4) ◽

pp. 822-831 ◽

Cited By ~ 129

Author(s):

Georg C. Schwabe ◽

Sigrid Tinschert ◽

Christian Buschow ◽

Peter Meinecke ◽

Gerhard Wolff ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Type B ◽

Kinase Gene ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene

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FLT4 Receptor Tyrosine Kinase Gene Mapping to Chromosome Band 5q35 in Relation to the t(2;5), t(5;6), and t(3;5) Translocations

Genes Chromosomes and Cancer ◽

10.1002/gcc.2870070306 ◽

1993 ◽

Vol 7 (3) ◽

pp. 144-151 ◽

Cited By ~ 14

Author(s):

Elina Armstrong ◽

Kumar Kastury ◽

Olga Aprelikova ◽

Florencia Bullrich ◽

Christian Nezelof ◽

...

Keyword(s):

Tyrosine Kinase ◽

Gene Mapping ◽

Receptor Tyrosine Kinase ◽

Chromosome Band ◽

Kinase Gene ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene

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Új célzott terápiás lehetőség az onkológiában: tropomiozin receptor-tirozin-kináz gátlók

Orvosi Hetilap ◽

10.1556/650.2021.32183 ◽

2021 ◽

Vol 162 (34) ◽

pp. 1362-1369

Author(s):

Edina Kiss ◽

Zsuzsanna Pápai

Keyword(s):

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

First Generation ◽

Kinase Inhibitor ◽

Disease Free Survival ◽

Diagnostic Methods ◽

Molecular Diagnostic ◽

Precision Oncology ◽

Gene Fusions ◽

Trk Inhibitors

Összefoglaló. A molekuláris diagnosztikai módszerek folyamatos fejlődésének köszönhetően egyre több onkogén genetikai eltérést azonosítanak. A neurotrofikus tropomiozin receptor-tirozin-kináz (NTRK-) génfúziók fontos precíziós onkológiai célpontok, melyek mindhárom NTRK-génben előfordulhatnak, onkogén-hajtóerőként viselkednek. A génfúziók különböző molekuláris diagnosztikai módszerekkel azonosíthatók, melyek közül a legpontosabb, legköltségesebb és legidőigényesebb meghatározást az újgenerációs szekvenálási technika jelenti. A tropomiozin receptor-tirozin-kináz (TRK-) fúziós fehérjék szelektív gátlása személyre szabott onkológiai kezelési lehetőséget jelent a tumor típusától, lokalizációjától és a beteg életkorától függetlenül. Az első generációs TRK-gátlók gyors, hatékony és tartós daganatellenes hatást biztosítanak kimutatott NTRK-fúzió-pozitív daganatok esetén, alacsony mellékhatásprofil mellett. Az első generációs TRK-gátlók mellett jelentkező ’on target’ rezisztenciát a második generációs TRK-gátlók oldják fel. Szekvenciális tirozin-kináz-inhibitor-kezeléssel tartós betegségmentes túlélés érhető el. Orv Hetil. 2021; 162(34): 1362–1369. Summary. Due to the continuous development of molecular diagnostic methods, more and more oncogenic genetic abnormalities are being identified. Neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene fusions are important precision oncology targets that can occur in all three NTRK genes and act as oncogenic drivers. Gene fusions can be identified by a variety of molecular diagnostic technologies, of which next-generation sequencing is the most accurate, costly and time-consuming determination. Selective inhibition of tropomyosin receptor tyrosine kinase (TRK) fusion proteins represents a personalized oncology treatment option regardless of tumour type, localization and patient age. First-generation TRK inhibitors provide rapid, efffective and long-lasting antitumor activity in NTRK fusion-positive tumors with a low side-effect profile. On target resistance to first-generation TRK inhibitors is resolved by second-generation TRK inhibitors. Durable disease-free survival can be achieved with sequential tyrosine kinase inhibitor therapies. Orv Hetil. 2021; 162(34): 1362–1369.

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Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction.

Genetics ◽

10.1093/genetics/128.2.251 ◽

1991 ◽

Vol 128 (2) ◽

pp. 251-267 ◽

Cited By ~ 4

Author(s):

R V Aroian ◽

P W Sternberg

Keyword(s):

Caenorhabditis Elegans ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Egf Receptor ◽

Kinase Gene ◽

Multiple Functions ◽

Tyrosine Kinase Gene ◽

Receptor Tyrosine Kinase Gene ◽

Epidermal Growth ◽

Mutant Phenotypes

Abstract The let-23 gene, which encodes a putative tyrosine kinase of the epidermal growth factor (EGF) receptor subfamily, has multiple functions during Caenorhabditis elegans development. We show that let-23 function is required for vulval precursor cells (VPCs) to respond to the signal that induces vulval differentiation: a complete loss of let-23 function results in no induction. However, some let-23 mutations that genetically reduce but do not eliminate let-23 function result in VPCs apparently hypersensitive to inductive signal: as many as five of six VPCs can adopt vulval fates, in contrast to the three that normally do. These results suggest that the let-23 receptor tyrosine kinase controls two opposing pathways, one that stimulates vulval differentiation and another that negatively regulates vulval differentiation. Furthermore, analysis of 16 new let-23 mutations indicates that the let-23 kinase functions in at least five tissues. Since various let-23 mutant phenotypes can be obtained independently, the let-23 gene is likely to have tissue-specific functions.

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