| dc.description.abstract |
<p>Gliomas of the brainstem and closely surrounding structures are a devastating form
of brain cancers with some of the highest mortality rates among all cancers. The delicate
structures surrounding these tumors make surgical resection rare due to the risk of
perioperative mortality or paralysis. A lack of available tissue has created a dearth
of genomic information regarding gliomas effecting specific structures in the brainstem
impacting options for intervention.</p><p>This work comprises two major projects of
brainstem gliomas. The first part is to utilize next generation sequencing technique
to discover novel oncogenes, and to use epigenetic features to characterize brainstem
gliomas. The second part is to utilize integrated analysis of whole genome sequencing,
methylation microarray, RNA sequencing data to establish the classification of brainstem
gliomas.</p><p>In the first part we completed exomic and Sanger sequencing on 33 brainstem
gliomas and 17 thalamic gliomas to reveal major findings regarding their respective
oncogenomes. We reported the presence of IDH1 mutations occurring in brain- stem gliomas
exclusive of H3.3 mutations. We further revealed somatic mutations to PPM1D, the gene
encoding for the Protein phosphatase 1D in 37.5% of brainstem gliomas harboring H3.3
mutations. We determined that PPM1D mutations are mu- tually exclusive with TP53 mutations
in brainstem gliomas. This was the largest body of genomic work completed on specific
loci within the brainstem providing new insights into their respective oncogenomes
and presents PPM1D as a new oncotarget.</p><p>In the second part we then performed
a comprehensive study incorporating com- bined epigenetic and genomic analyses with
clinical features, aiming to understand the genetics and molecular biology of this
disease. From DNA methylation data, we identified four distinct clusters termed H3-Pons,
H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles.
The majority of tumors within H3-Pons and H3-Medulla harbored H3F3A mutations, but
showed distinct methy- lation patterns that correlated with anatomical localization
of these tumors within the pons or medulla, respectively. Clinical data also showed
significantly different overall survival between these clusters, and pathway analysis
demonstrated different mechanisms in these samples. In summary, we performed a comprehensive
molecular profiling study on a large brainstem glioma cohort, including Diffuse Intrinsic
Pon- tine Gliomas. Our findings indicate that the integration of DNA methylation data
may facilitate a better understanding of brainstem glioma classification and guide
future studies for the development of novel treatments for this disease.</p>
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