Work

Uncoupling of gene expression from copy number presents therapeutic opportunities in aneuploid cancers

Year: 2021

Type: article

Abstract: The high degree of aneuploidy in cancer is likely tolerated via extensive uncoupling of copy number (CN) and mRNA expression (UCNE) of deleterious genes located in copy number aberrations (CNAs). To test the extent and role of UCNE in cancer, we performed integrative analysis of multiomics data across The Cancer Genome Atlas (TCGA), encompassing ∼ 5000 individual tumors. We found many genes having UCNE, the degree of which are associated with increased oncogenic signaling, proliferation and immune-suppression. The occurrence of UCNE appears to be orchestrated by complex epigenetic and regulatory changes, with transcription factors (TFs) playing a prominent role. To further dissect the regulatory mechanisms, we developed a systems-biological approach to identify candidate TFs, which upon perturbation can offset UCNE and reduce tumor fitness. Applying our approach on TCGA data, we identified 20 putative targets, 45% of which were validated by independent sources. Among them are IRF1 , which plays a prominent role in anti-tumor immunity and response to immune checkpoint therapy, ETS1, TRIM21 and GATA3 , which are associated with anti-tumor immunity, tumor proliferation and metastasis. Together, our study indicates that UCNE is likely an important mechanism in cancer development that can be exploited therapeutically.

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2021.100349

Authors: Vakul Mohanty, Fang Wang, Gordon B. Mills, Ken Chen

Institutions: The University of Texas MD Anderson Cancer Center, Oregon Health & Science University, OHSU Knight Cancer Institute

Language: English

Topic: Cancer Genomics and Diagnostics

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,200