NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls

Solomon, James P.; Linkov, Irina; Rosado, Andrea; Mullaney, Kerry; Rosen, Ezra Y.; Frosina, Denise; Jungbluth, Achim A.; Zehir, Ahmet; Benayed, Ryma; Drilon, Alexander; Hyman, David M.; Ladanyi, Marc; Sireci, Anthony; Hechtman, Jaclyn F.

doi:10.1038/s41379-019-0324-7

Cited by 432 publications

(536 citation statements)

References 33 publications

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“…NTRK rearrangements are oncogenic events in a wide variety of human cancers, including common and rare tumour types such as infantile fibrosarcomas, lipofibromatosis‐like neural tumours and fibrosarcoma‐like uterine sarcomas . TPM3–NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA–NTRK1 , TPR–NTRK1 , RBPMS–NTRK3 and EML4–NTRK3 fusions are rare (Figure ).…”

Section: Fibrosarcoma‐like Uterine Sarcomamentioning

confidence: 99%

“…TPM3–NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA–NTRK1 , TPR–NTRK1 , RBPMS–NTRK3 and EML4–NTRK3 fusions are rare (Figure ). NTRK break‐points vary, but the full‐length coding sequence of the tyrosine kinase domain remains unaltered, with fusion leading to increased expression of the kinase domain …”

Section: Fibrosarcoma‐like Uterine Sarcomamentioning

confidence: 99%

“…[16][17][18] PDGFB encodes a growth factor that binds and activates PDGF receptor tyrosine kinases important in regulating embryonic development, cell proliferation, cell migration, survival and chemotaxis. 19 NTRK rearrangements are oncogenic events in a wide variety of human cancers, 17,[20][21][22][23][24] including common and rare tumour types such as infantile fibrosarcomas, 20 lipofibromatosis-like neural tumours 20 and fibrosarcoma-like uterine sarcomas. 22,24 TPM3-NTRK1 fusion is present in more than 60% of uterine sarcomas, while LMNA-NTRK1, TPR-NTRK1, RBPMS-NTRK3 and EML4-NTRK3 fusions are rare 22,24 (Figure 3).…”

Section: Introductionmentioning

confidence: 99%

“…NTRK break-points vary, but the full-length coding sequence of the tyrosine kinase domain remains unaltered, with fusion leading to increased expression of the kinase domain. 23 NTRK fusion-positive uterine sarcomas affect premenopausal women with a median age of 39 years. 22,24 Tumours arise mainly in the cervix and rarely the corpus and appear polypoid, tan-yellow and necrotic or tan-white and whorled.…”

Section: Introductionmentioning

confidence: 99%

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Uterine mesenchymal tumours: recent advances

Boroujeni

Chiang

2019

Histopathology

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Almost all uterine mesenchymal tumours have been historically classified as either smooth muscle or endometrial stromal neoplasms. Recent application of molecular techniques has identified numerous lesions with distinctive genetic abnormalities and clinicopathological characteristics. Newly discovered uterine sarcoma subtypes include high‐grade endometrial stromal sarcomas with BCOR genetic abnormalities, fibrosarcoma‐like uterine sarcomas with NTRK rearrangements and COL1A–PDGFRB fusions, as well as undifferentiated uterine sarcomas with SMARCA4 mutations. Novel PLAG1 and PGR fusions have been identified in subsets of myxoid and epithelioid leiomyosarcomas. Some uterine tumours resembling ovarian sex‐cord tumour harbour GREB1 and ESR1 rearrangements. Histological and immunophenotypical features as well as underlying genetic abnormalities defining these lesions are discussed.

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Section: Fibrosarcoma‐like Uterine Sarcomamentioning

confidence: 99%

Section: Fibrosarcoma‐like Uterine Sarcomamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Uterine mesenchymal tumours: recent advances

Boroujeni

Chiang

2019

Histopathology

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“…Accordingly, comparative performance data on the two different technologies and their proficiency to detect NTRK fusions are still very limited. This is particularly true for major RNA-based targeted sequencing approaches, which are best suited to identify a wide range of different fusion variants [17][18][19][20] in formalin-fixed, paraffin-embedded (FFPE) tissue with variable tumor cell content.…”

Section: Introductionmentioning

confidence: 99%

NTRKtesting: First results of theQuiP‐EQAscheme and a comprehensive map ofNTRKfusion variants and their diagnostic coverage by targetedRNA‐basedNGSassays

Kirchner

Glade

Lehmann

et al. 2020

Genes Chromosomes & Cancer

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Gene fusions involving the three neurotrophic tyrosine receptor kinase genes NTRK1, NTRK2, or NTRK3 were identified as oncogenic drivers in many cancer types. Two small molecule inhibitors have been tested in clinical trials recently and require the detection of a NTRK fusion gene prior to therapeutic application. Fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (tNGS) assays are commonly used for diagnostic profiling of gene fusions. In the presented study we applied an external quality assessment (EQA) scheme in order to investigate the suitability of FISH and RNA-/DNA-based tNGS for detection of NTRK fusions in a multinational and multicentric ring trial. In total 27 participants registered for this study.Nine institutions took part in the FISH-based and 18 in the NGS-based round robin test, the latter additionally subdivided into low-input and high-input NGS methods (regarding nucleic acid input). Regardless of the testing method applied, all participants received tumor sections of 10 formalin-fixed and paraffin-embedded (FFPE) tissue blocks for in situ hybridization or RNA/DNA extraction, and the results were submitted via an online questionnaire. For FISH testing, eight of nine (88.8%) participants, and for NGS-based testing 15 of 18 (83.3%) participants accomplished the round robin test successfully. The overall high success rate demonstrates that FISHand tNGS-based NTRK testing can be well established in a routine diagnostic setting.Complementing this dataset, we provide an updated in silico analysis on the coverage of more than 150 NTRK fusion variants by several commercially available RNA-based tNGS panels. K E Y W O R D S FISH, NGS, NTRK, NTRK fusion variants, RNA sequencing Albrecht Stenzinger and Nicole Pfarr are co-senior authors.

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Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas

et al. 2023

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ImportanceThyroid epithelial malignant neoplasms include differentiated thyroid carcinomas (papillary, follicular, and oncocytic), follicular-derived high-grade thyroid carcinomas, and anaplastic and medullary thyroid carcinomas, with additional rarer subtypes. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has fostered developments in precision oncology, with the approval of tropomyosin receptor kinase inhibitors (larotrectinib and entrectinib) for patients with solid tumors, including advanced thyroid carcinomas, harboring NTRK gene fusions.ObservationsThe relative rarity and diagnostic complexity of NTRK gene fusion events in thyroid carcinoma present several challenges for clinicians, including variable access to robust methodologies for comprehensive NTRK fusion testing and poorly defined algorithms of when to test for such molecular alterations. To address these issues in thyroid carcinoma, 3 consensus meetings of expert oncologists and pathologists were convened to discuss diagnostic challenges and propose a rational diagnostic algorithm. Per the proposed diagnostic algorithm, NTRK gene fusion testing should be considered as part of the initial workup for patients with unresectable, advanced, or high-risk disease as well as following the development of radioiodine-refractory or metastatic disease; testing by DNA or RNA next-generation sequencing is recommended. Detecting the presence of NTRK gene fusions is important to identify patients eligible to receive tropomyosin receptor kinase inhibitor therapy.Conclusions and RelevanceThis review provides practical guidance for optimal integration of gene fusion testing, including NTRK gene fusion testing, to inform the clinical management in patients with thyroid carcinoma.

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NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls

Cited by 432 publications

References 33 publications

Uterine mesenchymal tumours: recent advances

Uterine mesenchymal tumours: recent advances

NTRKtesting: First results of theQuiP‐EQAscheme and a comprehensive map ofNTRKfusion variants and their diagnostic coverage by targetedRNA‐basedNGSassays

Diagnosis and Management of Tropomyosin Receptor Kinase Fusion-Positive Thyroid Carcinomas

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