Genetic susceptibility plays a significant role in glioma development. An individual with two or more first- and/or
second-degree affected relatives has a two-fold increased risk of the disease. We were the first to suggest
mutations in POT1 (Protection of Telomeres 1) as causative in familial glioma (FG). We have now established
the presence of POT1 mutations in 5 different families, providing the strongest evidence of its role in glioma.
However, we do not yet have direct functional evidence that loss of POT1 is causal in glioma leaving few
options for carrier surveillance or potential treatment targets. We are currently able to explain the genetic basis
of glioma in up to 12% of our families, using highly stringent criteria for calling a mutation deleterious and
causal. In contrast, the majority of our families remain unexplained though several candidate genes have
emerged as `suspects of interest (SOIs)'.
We propose a data-driven, knowledge-based, computational approach to guide candidate gene selection for
functional characterization. In order to further our efforts to explain the genetic basis of FG we propose two
specific aims to: Identify new gene candidates that may cause FG through WGS (Aim 1). We will identify
SNVs, small indels, and structural variants in both coding and noncoding regions of the genome, intensively
annotate those variants using more than 50 data sources, and we will rank these variants using multiple criteria
based on their likelihood to cause disease. In addition to the 270 FG cases (from 203 FG families) with
sequence data already available, we will also sequence an additional 100 cases (from 100 families) already
collected in our Glioma International Case-Control Study with a reported family history using Gliogene criteria,
and 200 newly recruited cases (from 100 families) with a strong family history of glioma to enhance our
discovery. ). We will molecularly characterize tumor samples when available to enable analysis of our cohort
by tumor subtype. The second aim is to functionally validate SOIs to include: A) POT1 mutations identified in
additional families and B) newly discovered FG susceptibility genes (SOIs) from Aim 1 using our novel
experimental mouse stem cell spheres and mouse models of gliomagenesis.To determine the functional
contributions of POT1 and novel mutations identified in our WGS studies, we will evaluate these genes in
glioma mouse models using CRISPR gene editing technology.
This study has the strong potential for delineating the genetic basis of glioma for genetic testing of high-risk
families; success will offer insight on the underlying biology of glioma for future work on early detection and
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