Despite considerable molecular heterogeneity, all diffuse gliomas are incurable at present, signaling an urgent
need for improved understanding of glioma biology. Even with recent advances, functional and clinically
relevant correlations between somatic and germline genetics in glioma remain virtually nonexistent. In
particular, the extent to which any or all glioma risk alleles drive the development of somatically designated
glioma subclasses is largely unknown. This proposal builds on our extensive collaborative experience with the
germline characterization of glioma, and leverages an existing repository of sporadic glioma patients accrued
from two of the nation's largest cancer centers (MD Anderson (MDA) and Memorial Sloan Kettering (MSK)).
These resources ideally position us to examine the interaction of germline and somatic genetics in glioma
evolution. Most existing large-scale profiling efforts, including those of the Cancer Genome Atlas (TCGA), lack
extensive information on disease treatment and progression along with genome-wide germline polymorphism
data. We propose to molecularly profile 1,350 cases from a set of over 2,000 glioma patients treated at our
institutions with: 1) readily available tumor tissue; 2) stored germline DNA; and 3) detailed clinical data
including treatment information, disease progression, and survival. Importantly, we have already obtained high-
density germline single nucleotide polymorphism (SNP) data for these patients using the Illumina OncoArray
platform. We now propose to conduct focused and comprehensive molecular profiling on tumor tissue
ascertained from this patient cohort to correlate both glioma subclass and patterns of somatic alterations with
germline risk alleles and clinical outcome measures. Our overall hypothesis is that glioma susceptibility alleles
will correlate with distinct sets of somatic alterations and predict disease evolution and outcomes both between
and within molecularly designated glioma subclasses. We propose the following specific aims: Aim 1.
Determine the spectrum of germline susceptibility alleles associated with molecularly and clinically distinct
glioma subclasses. Aim 2. Refine risk stratification by correlating germline susceptibility alleles with specific
somatic alterations within individual glioma subclasses. Our findings should lead to significant innovation in
how gliomas are conceptualized, from the perspectives for both molecular pathogenesis and patient
management. Robust associations between germline genetics, molecular subclass, and somatic alterations
will provide novel insights into how distinct tumor subtypes arise in specific patient populations and even point
toward strategies for therapeutic development by identifying early-stage, pre-transformative sequences of
molecular events. Moreover, these data could also enable targeted surveillance and early detection in at-risk
populations, a management strategy that remains strikingly underexplored for glioma patients and, accordingly,
has the potential to be paradigm-shifting.
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