Clinical significance of <i>NTRK</i> family gene expression in neuroblastomas

Light, Jennifer E.; Koyama, Hiroshi; Minturn, Jane E.; Ho, Ruth; Simpson, Anisha M.; Iyer, Radhika; Mangino, Jennifer; Kolla, Venkatadri; London, Wendy B.; Brodeur, Garrett M.

doi:10.1002/pbc.23343

Cited by 28 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also evaluated MYC and MYCN expression, which are downregulated in RA-sensitive cells by 13- cis RA(33, 34), and NTRK1 and NTRK2, which are upregulated in response to 13- cis RA(35). Expression of these proteins in primary tumors correlates with clinical outcomes(36, 37). We confirmed the increase of PBX1 expression, observed as isoforms PBX1a and PBX1b, in RA-sensitive cell lines treated with 13- cis RA, and associated with changes in MYCN, MYC, NTRK1, and/or NTRK2 (Figure 2A–C).…”

Section: Resultsmentioning

confidence: 99%

PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid–Mediated Differentiation in Neuroblastoma

Shah

Wang

Selich‐Anderson

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Neuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance, and the normal differentiation pathway, are poorly understood. Three-Amino-acid Loop Extension (TALE) family genes are master regulators of differentiation. Since retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma. Experimental Design We evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13cis-RA treatment, identifying genes whose expression correlate with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by RT-qPCR, and three independent clinical cohort microarray datasets. Results We confirmed induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in NB cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histological neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts. Conclusions PBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors.

show abstract

Section: Resultsmentioning

confidence: 99%

PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid–Mediated Differentiation in Neuroblastoma

Shah

Wang

Selich‐Anderson

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Like TrkB, TrkA and TrkC are up-regulated in many types of cancers and demonstrated to be oncogenic as well (13). For example, Light et al (87) reported TrkA up-regulation in neuroblastomas was associated with poor prognosis, while activated expression and signaling of TrkC corresponded to a more aggressive and invasive neuroblastoma. Besides, the kinase domain of the three receptors are remarkably conservative.…”

Section: Clinical Trials Of Targeting Trk Receptors For Treatment Of mentioning

confidence: 99%

Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)

Meng

Liu

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

Neurotrophins are a family of growth factors that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4. Among them, BDNF is the most studied due to its high expression in the brain. Over the past two decades, BDNF and its receptor tropomyosin receptor kinase B (TrkB) have been reported to be upregulated in a wide range of tumors. This activated signal stimulates a series of downstream pathways, including phosphoinositide 3-kinase/protein kinase B, Ras-Raf-mitogen activated protein kinase kinase-extracellular signal-regulated kinases, the phospholipase-C-γ pathway and the transactivation of epidermal growth factor receptor. Activation of these signaling pathways induces oncogenic effects by increasing cancer cell growth, proliferation, survival, migration and epithelial to mesenchymal transition, and decreasing anoikis, relapse and chemotherapeutic sensitivity. The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.

show abstract

“…In addition, TRKC and very recently TRKB have also been shown to form oncogenic chimeras in multiple tumor types [12,13]. Aside from gene fusions, only an in-frame deletion of NTRK1 in acute myeloid leukemia and a splice variant of NTRK1 in neuroblastoma have been functionally characterized as oncogenic to date [14][15][16][17][18]. However, no reports are available on the effects of NTRK gene amplification (defined as ≥ 4.0 copies).…”

Section: Introductionmentioning

confidence: 99%

NTRK gene amplification in patients with metastatic cancer

et al. 2017

View full text Add to dashboard Cite

Purpose: Neurotropic tropomyosin receptor kinase (NTRK) fusions have been identified in a variety of cancers, and tyrosine kinase inhibitors targeting the tropomyosin receptor kinase (TRK) receptor are currently in clinical trials. However, no reports are available on the effects of NTRK gene amplification. Methods: Samples from patients enrolled in the sequencing program were analyzed using a next-generation sequencing (NGS) cancer panel. For cases in which NTRK amplification (defined as ≥ 4.0 copies) was identified, panTRK immunohistochemical (IHC) staining of tissue microarrays was performed. Results: A total of 1,250 tumor specimens collected between February 2014 and January 2016 were analyzed using the NGS cancer panel. NTRK amplification was detected in 28 cases of various types of cancer. Among 27 cases, only four were positive for pan-TRK IHC. These four cases were melanoma, sarcoma, lung cancer, and gastric cancer. We found that 2.2% of cancer patients showed NTRK amplification using NGS cancer panel and NTRK amplification resulted in protein overexpression in 14.8% of these patients. Conclusion: Patients with NTRK amplification and increased TRK protein expression may be considered for inclusion in clinical trials for NTRK inhibitors.

show abstract

Clinical significance of NTRK family gene expression in neuroblastomas

Cited by 28 publications

References 41 publications

PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid–Mediated Differentiation in Neuroblastoma

PBX1 Is a Favorable Prognostic Biomarker as It Modulates 13-cis Retinoic Acid–Mediated Differentiation in Neuroblastoma

Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)

NTRK gene amplification in patients with metastatic cancer

Contact Info

Product

Resources

About