NTRK1 Fusion in Glioblastoma Multiforme

Jinkuk Kim,Gye-Hyun Cho,Jaeyeol An,Young-Hyeh Ko,Do-Hyun Nam,Young-Eun Lee,Hee-Jin Cho,Yeri Lee,Kyeung Min Joo,James Bradley Elder

doi:10.1371/journal.pone.0091940

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3′ exons of neurotrophic tyrosine kinase receptor type 1 (NTRK1, encoding TrkA) are fused to 5′ exons of the genes that are highly expressed in neuronal tissues, neurofascin (NFASC) and brevican (BCAN). The fusions preserved both the transmembrane and kinase domains of NTRK1 in frame. NTRK1 is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked NTRK1 expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated NTRK1-pathway activity. Lentiviral transduction of the NFASC-NTRK1 fusion gene in NIH 3T3 cells increased proliferation in vitro, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target.

Highlights

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor
Survey of Gene Fusions in GBMs To search for novel gene fusions in GBM, we analyzed pairedend RNA-Seq data of 162 GBM patients, available through The Cancer Genome Atlas (TCGA) [7]
Because FGFR3-TACC3 was recently reported as a key oncogenic driver in the GBMs that harbor the fusion [6], our rediscovery of this fusion confirmed the validity of our analytic approach

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor. The current established first-line therapy––surgical resection and adjuvant chemoradiotherapy with temozolomide––provides mostly palliation, and the five year survival rate of GBM patients is only ,10% [1]. There is an urgent need to identify novel molecular targets that can be critical for GBM initiation and progression. Gene fusion has been known to be critical cancer driver mutation in hematopoetic-origin tumors [2]. Recent studies have shown that these fusion events occur in various types of solid tumors [3,4,5,6]. Many of the recent discoveries of the fusions were powered by massively parallel sequencing of cancer genome, exome, or transcriptome [5,6]. With the availability of large-scale sequencing data from public cancer sequencing projects, such as The Cancer Genome Atlas (TCGA) [7], the discovery of novel fusion genes or other important alteration events is becoming increasingly dependent on the use of sophisticated analytic strategies

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Results

Conclusion