TY - JOUR
T1 - Uncoupling of gene expression from copy number presents therapeutic opportunities in aneuploid cancers
AU - CTD2 Research Network
AU - Mohanty, Vakul
AU - Wang, Fang
AU - Mills, Gordon B.
AU - Chen, Ken
N1 - Funding Information:
This work was supported by the National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development (CTDˆ2) initiative. This work was supported in part by the NIH ( U01 CA247760 ) and the CPRIT ( RP180248 ) to K.C., the NCI Cancer Center Support Grant ( P30 CA016672 ), and NCI U01 CA217842 to G.B.M. The results published here are based in part upon data generated by Cancer Target Discovery and Development (CTD 2 ) Network ( https://ocg.cancer.gov/programs/ctd2/data-portal ) established by the National Cancer Institute’s Office of Cancer Genomics.
Funding Information:
This work was supported by the National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development (CTD?2) initiative. This work was supported in part by the NIH (U01 CA247760) and the CPRIT (RP180248) to K.C. the NCI Cancer Center Support Grant (P30 CA016672), and NCI U01 CA217842 to G.B.M. The results published here are based in part upon data generated by Cancer Target Discovery and Development (CTD2) Network (https://ocg.cancer.gov/programs/ctd2/data-portal) established by the National Cancer Institute's Office of Cancer Genomics. V.M. and K.C. designed the study. V.M. and F.W. performed the analysis. V.M. K.C. F.W. and G.B.M. helped analyze the results. All authors helped to write the manuscript. All authors have read and approved this paper. G.B.M. is a SAB/Consultant at AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, Zentalis Pharmaceuticals; has stock/options/financial from Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda; has licensed technology with HRD assay to Myriad Genetics, DSP patents with Nanostring; has sponsored research with Nanostring Center of Excellence, Ionis (provision of tool compounds); and has clinical trials support (funding or in kind) from AstraZeneca, Genentech, GSK, Lilly.
Publisher Copyright:
© 2021 The Authors
PY - 2021/7/20
Y1 - 2021/7/20
N2 - Uncoupling of mRNA expression from copy number (UECN) might be a strategy for cancer cells to a tolerate high degree of aneuploidy. To test the extent and role of UECN across cancers, we perform integrative multiomic analysis of The Cancer Genome Atlas (TCGA) dataset, encompassing ∼5,000 individual tumors. We find UECN is common in cancers and is associated with increased oncogenic signaling, proliferation, and immune suppression. UECN appears to be orchestrated by complex regulatory changes, with transcription factors (TFs) playing a prominent role. To further dissect the regulatory mechanisms, we develop a systems-biology approach to identify candidate TFs, which could serve as targets to disrupt UECN and reduce tumor fitness. Applying our approach to TCGA data, we identify 21 putative targets, 42.8% of which are validated by independent sources. Together, our study indicates that UECN is likely an important mechanism in development of aneuploid tumors and might be therapeutically targetable.
AB - Uncoupling of mRNA expression from copy number (UECN) might be a strategy for cancer cells to a tolerate high degree of aneuploidy. To test the extent and role of UECN across cancers, we perform integrative multiomic analysis of The Cancer Genome Atlas (TCGA) dataset, encompassing ∼5,000 individual tumors. We find UECN is common in cancers and is associated with increased oncogenic signaling, proliferation, and immune suppression. UECN appears to be orchestrated by complex regulatory changes, with transcription factors (TFs) playing a prominent role. To further dissect the regulatory mechanisms, we develop a systems-biology approach to identify candidate TFs, which could serve as targets to disrupt UECN and reduce tumor fitness. Applying our approach to TCGA data, we identify 21 putative targets, 42.8% of which are validated by independent sources. Together, our study indicates that UECN is likely an important mechanism in development of aneuploid tumors and might be therapeutically targetable.
KW - CNVs
KW - TCGA
KW - aneuploidy
KW - cancer biology
KW - immune evasion
KW - target discovery
KW - transcriptional regulation
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U2 - 10.1016/j.xcrm.2021.100349
DO - 10.1016/j.xcrm.2021.100349
M3 - Article
C2 - 34337565
AN - SCOPUS:85110462795
SN - 2666-3791
VL - 2
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 7
M1 - 100349
ER -