Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors

Sigal, Darren; Bhangoo, Munveer S.; Hermel, Jonathan A.; Pavlick, Dean C.; Frampton, Garrett M.; Miller, Vincent A.; Ross, Jeffrey S.; Ali, Siraj M.

doi:10.18632/oncotarget.26260

Cited by 41 publications

(37 citation statements)

References 17 publications

(14 reference statements)

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“…However, DNA and RNA sequencing of the two first patients demonstrate the introduction of premature stop codons by these fusions and a lack of transcription (Figure ), which is tantamount to a loss‐of‐function of the chimeric proteins due to the absence of tyrosine kinase domains. Frameshifts in NTRK fusion transcripts have been reported in only a single case of a primary undifferentiated neuroendocrine carcinoma so far . Finally, the third case exemplifies a recombined transcript whose functionality cannot be assessed by our analysis, although the absence of both an endogenous start codon and detectable RNA makes subsequent translation highly unlikely.…”

Section: Discussionmentioning

confidence: 80%

NTRK fusions in osteosarcoma are rare and non‐functional events

Ameline

Saba

Kováč

et al. 2020

The Journal of Pathology CR

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Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan-NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non-functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan-NTRK TKIs.

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Section: Discussionmentioning

confidence: 80%

NTRK fusions in osteosarcoma are rare and non‐functional events

Ameline

Saba

Kováč

et al. 2020

The Journal of Pathology CR

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“…A recent study investigating the contribution of NTRK fusions in neuroendocrine tumors reported six cases, originating from various anatomic sites that include the pancreas, uterus, and lung [68]. Interestingly, in three patients, the NTRK fragment was 5′ to its fusion partner.…”

Section: Ntrk Oncofusionsmentioning

confidence: 98%

“…Surprisingly, this patient also had a cooccurring KRAS Q61P mutation. The presence of cooccurring mutations with driver tyrosine kinase alterations has been rarely reported [67,68]. Nonetheless, this scenario warrants that cooccurring mutations with NTRK alterations should be considered as they may pose a resistance liability and limit durability of the response.…”

Section: Ntrk Oncofusionsmentioning

confidence: 99%

Revisiting NTRKs as an emerging oncogene in hematological malignancies

et al. 2019

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NTRK fusions are dominant oncogenic drivers found in rare solid tumors. These fusions have also been identified in more common cancers, such as lung and colorectal carcinomas, albeit at low frequencies. Patients harboring these fusions demonstrate significant clinical response to inhibitors such as entrectinib and larotrectinib. Although current trials have focused entirely on solid tumors, there is evidence supporting the use of these drugs for patients with leukemia. To assess the broader applicability for Trk inhibitors in hematological malignancies, this review describes the current state of knowledge about alterations in the NTRK family in these disorders. We present these findings in relation to the discovery and therapeutic targeting of BCR-ABL1 in chronic myeloid leukemia. The advent of deep sequencing technologies has shown that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Efficacy of Trk inhibitors has been demonstrated in NTRK-fusion positive human leukemia cell lines and patient-derived xenograft studies, highlighting the potential clinical utility of these inhibitors for a subset of leukemia patients.

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“… 1 ∗ Gene nomenclature and chromosomal localizations are described according to the Human Genome Nomenclature Committee database; 5′ fusion partners associated with more than one NTRK gene are in bold; fusions in which the NTRK gene is listed as the 5′ partner are not included. 39 † A brief history of NTRK fusions ( http://ntrkfusions.com/a-brief-history-of-ntrk-fusions , last accessed February 5, 2019). ‡ Loxo Oncology, Inc., data on file.…”

Section: Ntrk Genes In Cancermentioning

confidence: 99%

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Hsiao

Zehir

Sireci

et al. 2019

The Journal of Molecular Diagnostics

187

173

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Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/ neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.

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Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors

Cited by 41 publications

References 17 publications

NTRK fusions in osteosarcoma are rare and non‐functional events

NTRK fusions in osteosarcoma are rare and non‐functional events

Revisiting NTRKs as an emerging oncogene in hematological malignancies

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

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