Oncogenic context shapes the fitness landscape of tumor suppression
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Published:2023-10-12
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Blair Lily M.ORCID, Juan Joseph M., Sebastian Lafia, Tran Vy B., Nie Wensheng, Wall Gregory D., Gerceker Mehmet, Lai Ian K., Apilado Edwin A., Grenot Gabriel, Amar David, Foggetti Giorgia, Do Carmo Mariana, Ugur Zeynep, Deng Debbie, Chenchik Alex, Paz Zafra Maria, Dow Lukas E.ORCID, Politi Katerina, MacQuitty Jonathan J., Petrov Dmitri A., Winslow Monte M., Rosen Michael J.ORCID, Winters Ian P.ORCID
Abstract
AbstractTumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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