Detection of NTRK fusions in glioblastoma: fluorescent in situ hybridisation is more useful than pan-TRK immunohistochemistry as a screening tool prior to RNA sequencing

Bourhis, Amélie; Caumont, Charline; Quintin-Roué, Isabelle; Magro, Elsa; Dissaux, G.; Remoué, Annabelle; Noach, P.; Douet‐Guilbert, Nathalie; Seizeur, Romuald; Tyulyandina, Alexandra; Schick, Ulrike; Merlio, Jean-Philippe; Marcorelles, Pascale; Cappellen, David; Uguen, Arnaud

doi:10.1016/j.pathol.2021.05.100

Cited by 9 publications

(9 citation statements)

References 33 publications

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“…In cases with a suspicion of NTRK fusions, alternative FISH or NGS analysis is recommended. FISH is considered preferred to pan‐TRK immunohistochemistry as a screening test prior to RNA‐seq‐based NGS 22,23 . In the current study, NTRK3 rearrangement was identified by FISH using NTRK1/NTRK2/NTRK3 break‐apart probes.…”

Section: Discussionmentioning

confidence: 88%

Primary NTRK‐rearranged spindle cell neoplasm of bone harboring an HMBOX1::NTRK3 gene fusion

Wang

2023

Genes Chromosomes & Cancer

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The majority of neurotrophic tyrosine receptor kinase (NTRK) rearranged neoplasms occur either in the superficial or deep soft tissues of extremities or trunk. Occasionally, it arises in visceral organs. However, its occurrence as a primary osseous tumor has not been documented thus far. Herein, we describe a unique case of an NTRK rearranged neoplasm that presented as a primary bony lesion. The tumor occurred in a 21-year-old woman who presented with an increasing pain in the right lower extremity. Radiologic examinations revealed a destructive lytic lesion located in the lower portion of the right femur. Histologically, the tumor was composed of haphazard fascicles of monomorphic spindle cells displaying mild nuclear atypia and rare mitotic activity. Immunohistochemically, the tumor cells showed focal staining of pan-TRK and S100 protein. Fluorescence in situ hybridization analysis was performed with the utilization of break-apart probes for NTRK1/NTRK2/NTRK3 genes. An NTRK3 rearrangement was identified. Subsequent next-generation sequencing (RNA-seq) revealed HMBOX1exon6::NTRK3exon 14 fusion.Our study illustrates, albeit extremely rare, that NTRK-rearranged neoplasms can arise as a primary bone lesion. In addition, we describe a novel HMBOX1::NTRK3 fusion that has not been documented before.

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Section: Discussionmentioning

confidence: 88%

Primary NTRK‐rearranged spindle cell neoplasm of bone harboring an HMBOX1::NTRK3 gene fusion

Wang

2023

Genes Chromosomes & Cancer

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“…Screening of NTRK -fusions is usually performed at molecular level using NGS or FISH technique ( 12 ), DNA or RNA targeted testing. However, the molecular technique is costly, time-consuming, and unavailable in most centers, and sometimes associated with sampling errors due to nucleic acid degradation.…”

Section: Discussionmentioning

confidence: 99%

“…They do not provide additional information about the fusion partner. Instead, FISH technique was found more useful than Pan-Trk IHC as a screening tool to detect NTRK-fusion prior to RNA sequencing ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

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The Diagnostic Value of Pan-Trk Expression to Detect Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion in CNS Tumours: A Study Using Next-Generation Sequencing Platform

Mohamed¹,

Kurdi²,

Baeesa³

et al. 2022

Pathol. Oncol. Res.

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Background: Neurotrophic tyrosine receptor kinase (NTRK) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours.Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK-rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform.Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDHwildtype glioblastomas, four IDHmutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK-rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2-fusions (SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK-fusions. There was no statistically significant association between Pan-Trk expression and NTRK-fusion (p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK-fusion detection by using Pan-Trk IHC.Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK-fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method.

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“…Tumour samples devoid of the molecular alterations investigated by the IGFA were also included as negative controls with a particular selection of cases with atypical, doubtful or false positive FISH or IHC results. The FFPE tumour samples which served initially for IHC, FISH and RNA/DNA NGS analyses (and the results of these analyses: ALK, ROS1 and pan-TRK IHC; ALK, ROS1, RET, NTRK1, NTRK2, NTRK3 FISH; MET exon 14 skipping mutation and RNA Seq analyses using ARCHER Fusion Plex Lung kit on Illumina sequencing performed as described in our previous works) were collected for pursuing molecular analyses using the IGFA 15–19. Surgical and biopsy specimens with sufficient material (ie, allowing a new tissue section for an IGFA analysis) were selected.…”

Section: Methodsmentioning

confidence: 99%

Performances of the Idylla GeneFusion Assay: contribution to a rapid diagnosis of targetable gene fusions in tumour samples

et al. 2023

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AimsWe aimed to evaluate the performances of the Idylla GeneFusion Assay (IGFA) designed to detect, in a single, rapid and fully automated assay,ALK,ROS1,RET,NTRK1,NTRK2andNTRK3gene fusions andMETexon 14 skipping in cancer samples.MethodsBased on a set of tumours enriched in cases with gene fusions, we applied the IGFA to tumour areas of various sizes and tumour cell contents. IGFA results were compared with those obtained with other methods (immunohistochemistry, fluorescent in situ hybridisation, DNA and RNA next-generation sequencing).ResultsWe selected 68 tumours: 49 cases with known gene fusions (8ALK, 8ROS1, 5RET, 7NTRK1, 3NTRK2and 6NTRK3ones) orMETexon 14 skipping mutations (12 cases) and 19 cases with no fusion and noMETmutation. We performed 128 IGFA tests on distinct tissue areas. The global sensitivity and specificity of the IGFA were, respectively, 62.82% and 99.2% with variations between molecular targets and tissue areas. Of note, 72.5% sensitivity and 98.79% specificity were obtained in 37 tissue areas fulfilling the manufacturer’s recommendations (ie, at least 10% of tumour cells in at least 20 mm² of tissue area). The rate of non-conclusive results was higher in small samples with low percentages of tumour cells.ConclusionsThe IGFA could contribute to the rapid detection of targetable gene fusions and mutations, especially in context of rapidly growing cancers requiring urgent therapeutic choices.

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Detection of NTRK fusions in glioblastoma: fluorescent in situ hybridisation is more useful than pan-TRK immunohistochemistry as a screening tool prior to RNA sequencing

Cited by 9 publications

References 33 publications

Primary NTRK‐rearranged spindle cell neoplasm of bone harboring an HMBOX1::NTRK3 gene fusion

Primary NTRK‐rearranged spindle cell neoplasm of bone harboring an HMBOX1::NTRK3 gene fusion

The Diagnostic Value of Pan-Trk Expression to Detect Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion in CNS Tumours: A Study Using Next-Generation Sequencing Platform

Performances of the Idylla GeneFusion Assay: contribution to a rapid diagnosis of targetable gene fusions in tumour samples

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