Half the Chromosome It Used to Be - Identifying Cancer Treatments Targeting Aneuploid Losses

Sep 23, 2026

Aneuploidy is near-ubiquitous in cancer, reducing chemotherapy efficacy while sometimes sensitizing cells to other drugs. The study integrates data from The Cancer Genome Atlas (TCGA; 10,967 samples and 16,948 aneuploidy events) and the PRISM screen (578 cell lines and 4518 compounds) to systematically match treatments to aneuploid cancer states. Results reveal extensive aneuploidy–treatment, prognosis, and mechanism associations, highlighting pathway-altering compounds and glucocorticoid receptor agonists.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Introduction

Aneuploidy in Cancer Biology

Chemotherapy Resistance and Fitness Constraints

Abstract

Background/Objectives

Methods

Results

Conclusions

Article Half the Chromosome It Used to Be: Identifying Cancer Treatments Targeting Aneuploid Losses Andrew O. Disharoon and Joe R. Delaney * Academic Editor: David Gómez Matallanas Received: 20 May 2025 Revised: 11 June 2025 Accepted: 12 June 2025 Published: 14 June 2025 Citation: Disharoon, A.O.; Delaney, J.R. Half the Chromosome It Used to Be: Identifying Cancer Treatments Targeting Aneuploid Losses. Genes 2025, 16, 708. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/genes16060708](10.3390/genes16060708) Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA; [disharoa@musc.edu](disharoa@musc.edu) * Correspondence: [delaneyj@musc.edu](delaneyj@musc.edu); Tel.: +1-843-792-6575 Abstract: Background/Objectives: Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs. Methods: To systematically identify treatment strategies that target aneuploid cancers, data were integrated from The Cancer Genome Atlas (TCGA; 10,967 samples, 16,948 aneuploidy events) and the Broad Institute’s Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 578 cancer cell lines and 4518 compounds. Results: Our analyses uncovered 37,720 significant positive and negative associations linking specific aneuploidies and treatments with patient prognosis or cell viability. Within TCGA data, 22 treatments correlated with improved 5-year survival for specific aneuploid cancers, whereas 46 were linked to worse outcomes. A complementary analysis of PRISM identified 17,946 compound– aneuploidy associations and 16,189 mechanism of action (MOA)–aneuploidy associations. Pathway-altering compounds that selectively reduce viability in cells with aneuploidy profiles were discovered, including an unexpectedly prominent number of glucocorticoid receptor agonists. Conclusions: This integrated dataset provides a resource for designing therapeutic decision hypotheses, identifying drug-repurposing opportunities, and informing future studies aimed at targeting aneuploidy-induced vulnerabilities in cancer. Keywords: oncology; cancer; chemotherapy; precision oncology; aneuploidy 1. Introduction Cancer is largely a consequence of genomic dysregulation made pathogenic through successful evasion, expansion, and exploitation of its parent-host. While not exclusively the driver of oncogenesis [1], this genomic dysregulation arises from a range of factors, including single-point mutations and large-scale chromosomal abnormalities such as aneuploidy. Aneuploidy is the abnormal number of chromosomes or chromosome arms, differing from the normal diploid (euploid) state [2,3] . Aneuploidy includes both losses and gains of chromosomal material and is most often a change of a single allele, or monoallelic, in tumors. Aneuploidy is distinct from polyploidy, the gain or amplification of entire genomes across all chromosome arms, which can precede further aneuploid variation. Aneuploidy’s genesis as an instigator or consequence of cancer evolution is well documented [2,4–6] . The majority of cancers either display or have the potential to display some sort of aneuploidy [7] . For example, 17p monoallelic loss and subsequent loss of wild-type TP53, a tumor suppressor gene, is a major driver of lung, breast, ovarian, leukemia, colon, esophagogastric, and other cancers [8] . Zygosity is important for tumor suppressor genes. Loss of a wild-type tumor suppressor allele with retention of mutated allele is a frequent driving event for oncogenesis [9] . Aneuploidy incurs the accum

FAQs

What role does aneuploidy play in cancer and treatment response?

Aneuploidy is common in cancer and can decrease chemotherapy efficacy while also sensitizing cells to some drugs. Its presence is linked to broader genomic and chromosomal instability.

How were candidate treatment strategies systematically identified in the study?

The researchers integrated TCGA data (10,967 samples with 16,948 aneuploidy events) with the PRISM screen (578 cancer cell lines and 4518 compounds). This enabled association mapping between specific aneuploidies, treatments, and outcomes.

What were the key findings regarding drug–aneuploidy and prognosis associations?

The analyses identified 37,720 significant positive and negative associations connecting aneuploidies and treatments to patient prognosis or cell viability. In TCGA, 22 treatments correlated with improved 5-year survival while 46 linked to worse outcomes, and PRISM revealed extensive compound–aneuploidy and MOA–aneuploidy associations.

Sep 23, 2026

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