Date of Award

5-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Suzanne J. Baker, Ph.D.

Committee

Michael A. Dyer, Ph.D. Lawrence M. Pfeffer, Ph.D. Martine Roussel, Ph.D. Gerard P. Zambetti, Ph.D.

Keywords

ACVR1, cancer, gene fusions, glioma, NTRK

Abstract

Pediatric high-grade gliomas (pHGGs), with a two-year survival rate of less than 20%, are some of the most aggressive human cancers. This dissertation begins with our analysis of 127 pHGGs, including brainstem (BS) and non-brainstem (NBS) tumors, from 118 patients using next-generation sequencing technologies. Nearly one-third of BS-HGGs, also known as diffuse intrinsic pontine gliomas (DIPGs), harbored somatic heterozygous missense mutations in ACVR1, coding for a receptor serine-threonine kinase involved in bone morphogenetic protein (BMP) signaling. These alterations led to gain-of-function as evidenced by increased phosphorylation of downstream targets in primary astrocytes and zebrafish embryo ventralization. Whole-genome sequencing and RNASeq revealed that nearly half of our cohort contained structural variants. We identified recurrent gene fusions preserving the kinase domain of the neurotrophin family of receptor tyrosine kinases (NTRK) including three novel fusions and two fusions previously described in other tumor types. NTRK fusion genes were identified in 40% of infant (<3 years of age) NBS-HGGs, and 7% of pHGG overall. We also found that infants have significantly reduced mutation burdens when compared to pHGGs in older children, suggesting a small number of oncogenic mutations are required in infant tumors. These findings, coupled with the observation that infants have a better prognosis than non-infants, make infant NBS tumors a distinct subgroup of pHGG. NTRK gene fusions also occur in pediatric low-grade glioma (pLGG) and adult glioblastoma but are not as enriched as they are in infant NBS-HGG, and adult glioblastoma and non-infant pHGGs exhibit higher mutation rates than infant tumors. NTRK fusion genes are therefore gliomagenic drivers throughout various development settings; yet it appears as if gliomas driven by the same oncogenic lesion can vary in tumor phenotype as a function of contextual differences. With this in mind, we used genetically engineered mice with a NTRK gene fusion knock-in allele to generate HGG in vivo. Given that tumor is evident by early postnatal life (P5), this is, to our knowledge, the first report of a bona fide spontaneous pHGG model. The second part of this dissertation is the characterization of these tumors.

ORCID

http://orcid.org/0000-0002-5558-6825

DOI

10.21007/etd.cghs.2016.0396

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