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BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

Lopez-Garcia, C; Sansregret, L; Domingo, E; McGranahan, N; Hobor, S; Birkbak, NJ; Horswell, S; ... Swanton, C; + view all (2017) BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. Cancer Cell , 31 (1) pp. 79-93. 10.1016/j.ccell.2016.11.001. Green open access

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Abstract

Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.

Type: Article
Title: BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ccell.2016.11.001
Additional information: Copyright © 2017 The Author(s). Published by Elsevier Inc. This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, Chromosomal Instability, Genomic Instability, Breast-cancer, Microsatellite Instability, Multidrug-resistance, Genetic Instability, Tumor Suppression, Human-cells, DNA-damage, Mutations
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/1536093
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