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J Thorac Oncol. 2018 Dec 11. pii: S1556-0864(18)33512-3. doi: 10.1016/j.jtho.2018.12.003. [Epub ahead of print]

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK gene rearrangements.

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
2
Department of Medicine, MSKCC, New York, NY.
3
Department of Medicine, MSKCC, New York, NY; Human Oncology and Pathogenesis Program, MSKCC, New York, NY; Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
4
Department of Pathology, University Pittsburgh Medical Center, Pittsburgh, PA.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Human Oncology and Pathogenesis Program, MSKCC, New York, NY.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: antonesc@mskcc.org.

Abstract

BACKGROUND:

Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor ALK gene rearrangements and overexpress ALK protein. The wide application of next generation sequencing (NGS) and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMT.

DESIGN:

In this study we investigate a series of pediatric and adult thoracic IMT for abnormalities in a wide spectrum of actionable kinases, by applying a variety of molecular and NGS techniques, including FISH, targeted RNA sequencing and NanoString.

RESULTS:

There were 33 thoracic IMTs, with a mean age of 37, including 5 children. Tumors showed a monomorphic spindle cell phenotype, except one with epithelioid morphology and moderate to severe atypia. By IHC, 24 cases were ALK positive, of which by FISH, 19 showed ALK rearrangements and 1 RET gene rearrangement. RNA sequencing was performed in the remaining 4 cases lacking ALK abnormalities by FISH, revealing ALK fusions in 3 cases, involving TMP4 and EML4 genes. NanoString was performed in the remaining case, revealing ALK-alternative transcription initiation (ALKATI). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in 6 cases and ETV6-NTRK3 fusion in 3, respectively.

CONCLUSIONS:

By employing a battery of complementary molecular techniques, all thoracic IMTs harbored a tyrosine kinase abnormality, with 30% outside the ALK kinase, including gene fusions involving ROS1, NTRK3, and RET. We also describe for the first time ALKATI-induced ALK oncogenic activation is involved in the pathogenesis of IMTs.

KEYWORDS:

ALK; NTRK3; ROS1; fusion; inflammatory myofibroblastic tumor; kinase

PMID:
30550870
DOI:
10.1016/j.jtho.2018.12.003

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