Abstract 2263: Why does the loss of chromosomes 10 and the gain of 7 co-occur in gliomas

Abstract Introduction: Gliomas, including aggressive forms such as glioblastoma (GBM) and lower-grade gliomas (LGG), present formidable challenges for treatment. Since the late 1980’s it has been known that loss of chromosome 10 (10 loss) and gain of chromosome 7 (7 gain) often co-occur in GBM. The reasons for this frequently co-occurring event are not very clear, with some prior studies speculating on a few driver genes as culprits. In this study, we aim to study and understand the phenomenon of 10 loss and 7 gain in gliomas in a systematic, chromosome-wide level. Methods: Our analysis consists of three main analyses, that bring independent sources of evidence to address our research question: a) Analyzing data from Progenetix, we developed rigorous probabilistic models that elucidate the probability dynamics of 10 loss and 7 gain in gliomas. b) Next, by analyzing hundreds of genomic and transcriptomic samples from TCGA brain cancer patients, and cell lines, we identified a category of clinically relevant genetic interactions termed 'synthetic rescues'. Synthetic rescue (DU-SR) interactions refer to a form of functional interplay in which the detrimental impact on cell fitness caused by the inactivation of a specific gene (termed ‘vulnerable gene’) is compensated by upregulation of another gene (termed ‘rescuer gene’). The enrichment of rescuer genes on 7 for the vulnerable genes on 10 was then tested. c) Utilizing large-scale in vitro essentiality screens via CRISPR technology in central nervous system (CNS) cancer cell lines, we sought to investigate the fitness effects of different possible sequences of chromosomal 10 and 7 loss and gains. Results: The main results emerging from this three-pronged analysis are as follows: 1) We find that 7 gain after 10 loss is a more likely event than the opposite order of loss of 10 after 7 gain whose probability is explained by a random chance model. 2) We show that loss of 10 is enabled by the cells’ ability to readily mitigate its loss, specifically through rescue interactions with genes lying on the amplified 7 chromosome. 3) These findings in the analysis of patients’ tumors are further reinforced by an independent investigation in IDH wild-type CNS cancer cell line essentiality screens. Conclusions: The co-occurrence of 10 loss and 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair occurring in human cancer. Our analysis presents a new multi-pronged approach to analyze co-occurring aneuploidy events in cancer, showing the long-contemplated chromosomal co-occurrence events in gliomas, a mystery that has persisted for decades, is likely to arise from genetic rescue interactions between many genes that lie on those chromosomes. From a future translational standpoint, it additionally points to key rescuer genes that may be potentially targeted. Citation Format: Nishanth Ulhas Nair, Alejandro A. Schäffer, Michael E. Gertz, Kuoyuan Cheng, Avinash Das Sahu, Gil Leor, Eldad D. Shulman, Kenneth D. Aldape, Uri Ben-David, Eytan Ruppin. Why does the loss of chromosomes 10 and the gain of 7 co-occur in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2263.