Molecular classification has improved diagnosis and treatment for patients with malignant gliomas. However, classification has relied on individual assays that are both costly and slow, leading to frequent delays in treatment. Here, we propose the use of DNA methylation, as an emerging clinical diagnostic platform, to classify gliomas based on major genomic alterations and provide insight into subtype characteristics. We show that using machine learning models, DNA methylation signatures can accurately predict somatic alterations and show improvement over existing classifiers. The established Unified Diagnostic Pipeline (UniD) we develop is rapid and cost-effective for genomic alterations and gene expression subtypes diagnostic at early clinical phase and improves over individual assays currently in clinical use. The significant relationship between genetic alteration and epigenetic signature indicates broad applicability of our approach to other malignancies.

Kirsten rat sarcoma viral oncogene homolog ( KRAS ) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRAS ^G12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRAS ^G12V , partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRAS ^G12V - transgenic mouse model. We explored the therapeutic potential of KRAS ^G12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRAS ^G12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRAS ^G12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8 ⁺ T cells. Our work provides insights into the effect of KRAS ^G12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS -mutant cancers.