Abstract 1383: Defining the role of the Daam2 R414W germline variant in familial glioma.

Abstract Malignant glioma is the most common primary brain tumor in adults, with high morbidity and mortality due to its aggressive nature and limited treatment options. While advances in molecular genetics have improved glioma classification, these systems rely predominantly on sporadic somatic mutations that cannot predict individual glioma risk. In contrast, the 5-10% of gliomas occurring in families with hereditary predisposition offer a powerful opportunity to identify germline variants that increase glioma susceptibility and may serve as biomarkers for risk assessment. Dysregulation of developmental signaling pathways has been increasingly implicated in gliomagenesis. Through whole-exome sequencing of familial glioma patients, we identified five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2), a key regulator of Wnt signaling. Daam2 encodes a formin protein crucial for glial differentiation and highly enriched in glial cells. Our prior work demonstrated that Daam2 is sufficient to promote gliomagenesis and essential for glioma growth, prompting us to investigate whether these variants affect tumor progression. We overexpressed each variant in patient-derived glioma stem-like cells and orthotopically xenografted them into immunodeficient mice. Among the variants, Daam2-R414W significantly promoted tumor cell proliferation in vitro and in vivo. To model this patient-observed mutation in an immunocompetent system, we generated a Daam2-R414W knock-in mouse model. Mutant mice exhibited an increased number of proliferating glial progenitor cells in the subventricular zone compared to wildtype (WT) controls, suggesting that Daam2-R414W expands the glial progenitor pool to facilitate glioma initiation. Since the patient harboring the Daam2-R414W mutation was diagnosed with oligodendroglioma, a low-grade glioma (LGG), we induced LGG in Daam2-R414W mutant mice and observed increased tumor cell proliferation and decreased survival compared to WT LGG-bearing mice, suggesting that Daam2-R414W accelerates malignant progression. To identify molecular mechanisms underlying these phenotypes, we performed bulk RNA-sequencing on LGG tumors from Daam2-R414W mutant and WT mice. Sequencing revealed increased expression of Wnt pathway components, actin cytoskeletal genes, and oligodendrocyte progenitor cell (OPC) markers in Daam2-R414W tumors compared to WT. Among these changes, marked upregulation of TCF3, a key transcription factor in canonical Wnt signaling, points to enhanced pathway activation in mutant tumors. These findings suggest that Daam2-R414W accelerates tumor progression by amplifying Wnt-driven proliferative signaling programs that drive glioma growth. Overall, this study identifies a hereditary glioma-predisposing variant and demonstrates how germline mutations in developmental regulators can disrupt normal cellular function to promote malignancy. Citation Format: Tiffany J. Choy, Qi Ye, Melissa L. Bondy, Hyun Kyoung Lee. Defining the role of the Daam2 R414W germline variant in familial glioma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1383.