Primitive neuroectodermal tumors (PNET) include medulloblastoma and supratentorial
primitive neuroectodermal tumor subtypes that share histological features yet differ at the
genomic level and in clinical outcome. Delineation of the genetic anomalies between
PNET subtypes is a current challenge for establishing effective targeted therapeutic
strategies against these aggressive tumors. Current efforts have demonstrated specific
molecular pathways drive a minority of medulloblastoma and supratentorial PNET but
the genetic basis of the majority of these tumors remains poorly understood and
anecdotal. To better define the genetic causes of medulloblastoma and supratentorial
PNET, we have developed a single Sleeping Beauty transposon insertional mutagenesis
mouse model that recapitulates the morphological similarities and genetic heterogeneity
of these tumor types capable of identifying genetic drivers important for PNETagenesis.
This work has revealed biologically relevant candidate oncogenes and tumor suppressor genes for both medulloblastoma and supratentorial PNET in mice and humans.
ARHGAP36 is a novel oncogene implicated in poorly understood MB molecular
subgroups, and multiple RAS pathway effector genes were identified to be important for
sPNET formation. Ultimately, these results present new understanding of the genetic
basis for medulloblastoma and supratentorial PNET development and offer potential targets for therapeutic testing to improve patient clinical outcome.
University of Minnesota Ph.D. dissertation. December 2011. Major: Microbiology, Immunology and Cancer Biology. Advisor: Dr. David Andrew Largaespada. 1 computer file (PDF); xi, 131 pages.
Larson, Jon David.
Characterization of the primitive neuroectodermal tumor genome using transposon-mediated insertional mutagenesis..
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