Grant Number:	1R03CA309623-01 Interpret this number
Primary Investigator:	Diaz, Aaron
Organization:	University Of California, San Francisco
Project Title:	Annotating the Phenotypes of Variants Driving Embryonal Brain Tumors and Birth Defects
Fiscal Year:	2026

PROJECT SUMMARY Children with birth defects have a significantly higher incidence rate of embryonal brain tumors. However, the shared genetic defects that drive both pathologies are not fully understood. Shared driver genetic variants are incompletely annotated. Importantly, the cellular phenotypes induced by many driver variants are unknown. These critical gaps in our knowledge inhibit the development of diagnostic genetic tests, limit our ability to develop precision therapies and cloud our understanding of the etiologies of these diseases. This proposal leverages our preliminary studies of data and samples that are part of the Gabriella Miller Kids First Data Resource Center. We performed single-nucleus RNA and epigenetic assays from brain tumor tissues that were patient-matched to those sequenced for the Kids First Data Resource Center via whole-genome and whole- exome approaches. These patient-matched single-cell and bulk-sequencing data provide a unique opportunity to identify the cellular populations that harbor driver variants and understand how the presence of those variants alters gene expression and epigenetic phenotypes. The overall objective of this project is to annotate known and novel driver genetic variants that are shared between embryonal brain tumors and congenital diseases with gene expression and epigenetic signatures. In Aim 1, we annotate embryonal brain-tumor driver variants and their prevalence in populations with birth defects, using statistical metrics of selection pressure. In Aim 2, we Identify expression phenotypes and epigenetic signatures associated with brain-tumor driver variants and birth defect-associated variants in brain-tumor and non-malignant cell types, using our mated single-cell data and other spatial transcriptomics data. The rationale for these studies is twofold: firstly, we will identify novel variants that are drivers of brain tumor development and prevalent in populations with birth defects. Secondly, annotating the aberrant gene expression and epigenetic signatures induced by driver variants will allow us to identify the cell types critically affected by these variants and hypothesize about their functional effect. This project’s impact comes from combining multiple patient-matched genomics modalities. While some genes associated with both cancer and birth defects are known, our preliminary data indicate that this list is far from being comprehensive. Identifying mutations that both drive brain tumors and are associated with birth defects is significant because it enhances our understanding of the mechanisms underlying both conditions. This knowledge can lead to improved diagnostic tools and targeted therapies for affected individuals. Surprisingly little is known about how driver variants alter cellular phenotypes in cancer and in development or what cell types are significantly altered. This study bridges that gap by associating genotype to phenotype.





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