PMID- 30550870 OWN - NLM STAT- MEDLINE DCOM- 20200630 LR - 20211204 IS - 1556-1380 (Electronic) IS - 1556-0864 (Print) IS - 1556-0864 (Linking) VI - 14 IP - 5 DP - 2019 May TI - Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements. PG - 825-834 LID - S1556-0864(18)33512-3 [pii] LID - 10.1016/j.jtho.2018.12.003 [doi] AB - INTRODUCTION: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs. METHODS: In this study, we have investigated a series of pediatric and adult thoracic IMTs for abnormalities in a wide spectrum of actionable kinases by applying a variety of molecular and next-generation sequencing techniques, including fluorescence in situ hybridization (FISH), targeted RNA sequencing, and NanoString assay. RESULTS: There were 33 patients with thoracic IMTs, including five children; their mean age was 37. The tumors showed a monomorphic spindle cell phenotype, except for one with an epithelioid morphologic pattern and moderate to severe atypia. By immunohistochemistry, 24 tumors were ALK positive, and 19 of the 24 showed ALK rearrangements and one ret proto-oncogene gene (RET) rearrangement by FISH. RNA sequencing was performed in the remaining four cases lacking ALK abnormalities by FISH, revealing ALK fusions involving tropomyosin 4 gene (TMP4) and echinoderm microtubule associated protein like 4 gene (EML4) as partner in three cases. NanoString assay was performed in the remaining case, revealing ALK alternative transcription initiation (ALK(ATI)). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in six cases and ETS variant 6 gene (ETV6)-neurotrophic receptor tyrosine kinase 3 gene (NTRK3) fusion in three cases, respectively. CONCLUSIONS: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALK(ATI)-induced ALK oncogenic activation in IMTs. CI - Copyright (c) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Chang, Jason C AU - Chang JC AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Zhang, Lei AU - Zhang L AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Drilon, Alexander E AU - Drilon AE AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Chi, Ping AU - Chi P AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York. FAU - Alaggio, Rita AU - Alaggio R AD - Department of Pathology, University Pittsburgh Medical Center, Pittsburgh, Pennsylvania. FAU - Borsu, Laetitia AU - Borsu L AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Benayed, Ryma AU - Benayed R AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Travis, William D AU - Travis WD AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Ladanyi, Marc AU - Ladanyi M AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Antonescu, Cristina R AU - Antonescu CR AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: antonesc@mskcc.org. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P50 CA140146/CA/NCI NIH HHS/United States GR - P50 CA217694/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20181211 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (MAS1 protein, human) RN - 0 (Proto-Oncogene Mas) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM CIN - J Thorac Oncol. 2019 May;14(5):758-760. PMID: 31027738 MH - Adolescent MH - Adult MH - Aged MH - Anaplastic Lymphoma Kinase/*genetics MH - Child MH - Child, Preschool MH - Female MH - Gene Rearrangement/*genetics MH - Humans MH - Male MH - Middle Aged MH - Myofibroblasts/*pathology MH - Proto-Oncogene Mas MH - Thoracic Neoplasms/*genetics/pathology MH - Young Adult PMC - PMC6486847 MID - NIHMS1519593 OTO - NOTNLM OT - ALK OT - Fusion OT - Inflammatory myofibroblastic tumor OT - Kinase OT - NTRK3 OT - ROS1 COIS- Conflict of interest: none EDAT- 2018/12/15 06:00 MHDA- 2020/07/01 06:00 PMCR- 2020/05/01 CRDT- 2018/12/15 06:00 PHST- 2018/09/23 00:00 [received] PHST- 2018/11/28 00:00 [revised] PHST- 2018/12/02 00:00 [accepted] PHST- 2018/12/15 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2018/12/15 06:00 [entrez] PHST- 2020/05/01 00:00 [pmc-release] AID - S1556-0864(18)33512-3 [pii] AID - 10.1016/j.jtho.2018.12.003 [doi] PST - ppublish SO - J Thorac Oncol. 2019 May;14(5):825-834. doi: 10.1016/j.jtho.2018.12.003. Epub 2018 Dec 11.