Volume 83, Issue 1 pp. 109-115

Original Article

Spectrum of kinase gene rearrangements in a large series of paediatric inflammatory myofibroblastic tumours

Elena V Preobrazhenskaya,

Corresponding Author

Elena V Preobrazhenskaya

[email protected]

orcid.org/0000-0001-7800-013X

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

Address for correspondence: E V Preobrazhenskaya, N.N. Petrov Institute of Oncology, Pesochny, 68 Leningradskaya st., 197758 Saint Petersburg, Russia. e-mail: [email protected]Search for more papers by this author

Amina M Suleymanova,

Amina M Suleymanova

Institute of Pediatric Oncology, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia

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Ilya V Bizin,

Ilya V Bizin

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Fyodor A Zagrebin,

Fyodor A Zagrebin

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Alexandr A Romanko,

Alexandr A Romanko

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

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Evgeniya S Saitova,

Evgeniya S Saitova

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Rimma S Mulkidzhan,

Rimma S Mulkidzhan

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Evgeny N Imyanitov,

Evgeny N Imyanitov

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

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Elena V Preobrazhenskaya,

Corresponding Author

Elena V Preobrazhenskaya

[email protected]

orcid.org/0000-0001-7800-013X

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

Amina M Suleymanova,

Amina M Suleymanova

Institute of Pediatric Oncology, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia

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Ilya V Bizin,

Ilya V Bizin

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Fyodor A Zagrebin,

Fyodor A Zagrebin

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Alexandr A Romanko,

Alexandr A Romanko

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

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Evgeniya S Saitova,

Evgeniya S Saitova

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Rimma S Mulkidzhan,

Rimma S Mulkidzhan

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

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Evgeny N Imyanitov,

Evgeny N Imyanitov

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia

Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia

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First published: 18 April 2023

https://doi.org/10.1111/his.14912

Citations: 2

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Abstract

Introduction

Inflammatory myofibroblastic tumours (IMTs), being an exceptionally rare category of paediatric neoplasms, often contain druggable gene rearrangements involving tyrosine kinases.

Methods and results

This study presents a large consecutive series of IMTs which were analysed for the presence of translocations by the PCR test for 5′/3′-end ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3 unbalanced expression, variant-specific PCR for 47 common gene fusions and NGS TruSight RNA fusion panel. Kinase gene rearrangements were detected in 71 of 82 (87%) IMTs (ALK: n = 47; ROS1: n = 20; NTRK3: n = 3; PDGFRb: n = 1). The test for unbalanced expression had 100% reliability in identifying tumours with ALK fusions, but failed to reveal ROS1 rearrangements in eight of 20 (40%) ROS1-driven IMTs; however, ROS1 alterations were detectable by variant-specific PCR in 19 of 20 (95%) cases. ALK rearrangements were particularly common in patients below 1 year of age (10 of 11 (91%) versus 37 of 71 (52%), P = 0.039). ROS1 fusions occurred more often in lung IMTs than in tumours of other organs (14 of 35 (40%) versus six of 47 (13%), P = 0.007). Among 11 IMTs with no kinase gene rearrangement identified, one tumour demonstrated ALK activation via gene amplification and overexpression, and another neoplasm carried COL1A1::USP6 translocation.

Conclusions

PCR-based pipeline provides a highly efficient and non-expensive alternative for molecular testing of IMTs. IMTs with no detectable rearrangements need further studies.

Graphical Abstract

This study presents the largest series of inflammatory myofibroblastic tumours (IMTs), which were subjected to comprehensive analysis of kinase gene rearrangements. A combination of non-expensive PCR test for 5′/3′-end unbalanced gene expression, variant-specific PCR and NGS revealed gene fusions in 71 of 82 (87%) IMTs. Some rearrangements demonstrated age- and organ-dependent distribution.

Conflicts of interest

The authors declare no potential conflicts of interest.

Open Research

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supporting Information

Filename

Description

his14912-sup-0001-Supinfo.docxWord 2007 document , 547.2 KB

Table S1. Clinical characteristics of patients with IMT.

Table S2. Clinicopathologic and genetic characteristics of IMTs.

Table S3. Primers and probes for the 5′/3′-end unbalanced expression testing.

Table S4. Primers and probes for the detection of ALK fusions.

Table S5. Primers for the detection of IMT-specific ROS1, NTRK3, NTRK1 and PDGFRb fusions.

Figure S1. Distribution of IMTs according to patients age.

Table S6. Distribution of IMTs according to patients age.

Figure S2. Distribution of fusions according to patients age.

Table S7. Distribution of fusions according to patients age

Figure S3. IMT localizations in tumours with various rearrangements.

Table S8. IMT localizations in tumours with various rearrangements.

Figure S4. Distribution of gene fusions in IMTs of different localization.

Table S9. Distribution of gene fusions in IMTs of different localization.

Figure S5. Inflammatory myofibroblastic tumour IMT27 carrying ALK amplification. A, PCR RNA expression analysis revealed high RNA expression of both 5′- and 3′-ends of ALK transcript; IMT without ALK rearrangement (WT) was utilized for the comparison. B, ALK IHC by D5F3 antibody detected weak (+1) granular cytoplasmic reactivity. C, Digital droplet PCR (ddPCR) revealed approximately 2-fold excess of ALK gene copies in the IMT27 but not in ALK-WT control tumour sample; TMEM163 gene served as gene-referee for this ddPCR assay.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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Citing Literature

Volume83, Issue1

July 2023

Pages 109-115