Using germline and somatic genetics to elucidate glioma risk and improve patient outcomes - PROJECT SUMMARY Beginning in 2016 and expanding in 2021, the WHO Classification of Tumors of the Central Nervous System utilizes acquired tumor alterations to classify and grade adult diffuse glioma. Genomewide association studies (GWAS) have identified 30 total germline variants across Europeans and East Asians associated with risk of developing adult diffuse glioma and some with development of specific clinically relevant molecular subtypes. Interestingly, some of these germline variants reside in or near genes that also have acquired tumor alterations in brain tumors. While a GWAS by the three primary 2016 WHO clinical subtypes were conducted, clinical characteristics and outcome heterogeneity exist within each subtype. Furthermore, the updated 2021 WHO criteria now utilize acquired tumor alterations for determining tumor grade. Thus, a current gap is to evaluate the genetic predisposition of developing a brain tumor with these clinically relevant acquired alterations or a tumor with a high mutation burden. Additionally, the functional relevance of most of the 30 germline variants remains unknown, which limits knowledge regarding the biology of glioma and critical information to develop preclinical models. Thus, we will use deconvolution of bulk RNA expression data, single-cell sequencing data, and modern epigenetic data to evaluate all known and newly identified germline variants. We will also determine the clinical utility of germline variants via polygenic risk models. While the prevalence of adult diffuse glioma is too low to screen the general population, we propose that a screening test can be used on targeted populations where differential diagnosis is challenging. Second, we propose that germline variants can predict whether a brain tumor patient has a particular acquired tumor alteration, e.g., IDH mutation, prior to surgery. Third, our preliminary data shows that polygenic risk scores are associated with overall survival. We will utilize both in-house and publicly available data on patient-matched germline and tumor specimens from adult diffuse glioma patients to expand our previous work and answer these additional essential questions. The project has the following three aims: Aim 1: Identify and validate novel germline variants associated with development of adult diffuse glioma with clinically relevant acquired tumor alterations. Aim 2: Using in-silico approaches, fine- map and evaluate the functional impact of known and newly identified adult diffuse glioma germline variants, accounting for specificity of cell type. Aim 3: Develop and validate the clinical utility of a glioma polygenic risk score for differential diagnosis of indeterminate brain lesions and to predict prognosis, and a polygenic tumor subtype model for predicting acquired tumor alterations. Sex and genetic ancestry will be carefully considered. Overall, understanding the interaction between germline and acquired genetics is crucial for development of more accurate diagnosis, targeting of modern glioma therapeutics that leverage specific tumor alterations, and improving patient outcomes.
