Abstract 3718: Characterization of chromosomal instability-related dependencies through cell-specific metric for gene dosage compensation potential

Abstract Numerical chromosomal instability (n-CIN) is a defining characteristic of most human cancers with serious implications of large-scale alterations of the genome - such as chromosome arm level copy number changes. These kinds of somatic alterations are frequently targeting oncogenes and tumor suppressors, enriched in cancer driver events in order to shape the transcriptome in favor of tumor progression and proliferation. While oncogenes are mostly associated with copy number gains and tumor suppressors are more frequent in chromosome arm losses, neighboring genes are also affected in both cases. This collateral damage may be able to create synthetic lethal relationships and context-specific dependencies. Cancer cells might be able to avoid partial loss and gain-related lethal effects by triggering different dose compensation mechanisms, occurring at the genomic, epigenetic and post-translational levels, which leads to deviations across copy number and expression profiles. To propose a metric for dose compensation potential, we analyzed copy number and gene expression profiles of the Cancer Cell Line Encyclopedia in order to characterize cancer cell lines with the ability to compensate dependencies arising from chromosomal losses and gains. Our metric consists of the sum of gene expression residuals from linear model fits, describing how much a cell line tends to under or overexpress genes compared to what we expect from copy number counts. By comparing other publicly available datasets with our results, such as perturbation transcriptomics data from the LINCS-L1000 project and the DepMap genome-wide gene essentiality measurements, we aim to identify CIN-related therapeutic vulnerabilities associated with chromosome arm losses and gains. Besides finding potential target candidates, we show that our method is capable of finding well-known pathway-specific compensation mechanisms. As an example, we show a significant correlation between the activity of the Nonsense mediated decay (NMD) pathway and our proposed compensation potential score (CPS) of cancer cell lines. We propose our method to be used to detect context-specific dependencies associated with gene dosage compensation, and also able to provide pathway-level evidence - both novel and previously known from the literature. Citation Format: Péter Szikora, Ivan Fekete, María Victoria Ruiz-Pérez, Dóra Kállai, Csilla Hegedűs, Bence Szalai, Daniel Veres. Characterization of chromosomal instability-related dependencies through cell-specific metric for gene dosage compensation potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3718.