title: BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.
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.
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-García
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sansregret
authors.affiliation: Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK; Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Sebastijan
authors.initials: S
authors.lastname: Hobor
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK.
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.affiliation: Bioinformatics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Grönroos
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer System Biology, Centre for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Favero
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.affiliation: Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Sharmin
authors.initials: S
authors.lastname: Begum
authors.affiliation: Advanced Sequencing Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Phillimore
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Burrell
authors.affiliation: Research Department of Pathology, University College London Medical School, University Street, London WC1E 6JJ, UK.
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.affiliation: Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Kovac
authors.affiliation: Experimental Histopathology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.affiliation: Bioinformatics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Institute for Cancer Genetics and Informatics, Norwegian Radium Hospital, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway.
authors.forename: Havard
authors.initials: H
authors.lastname: Danielsen
authors.affiliation: Research Department of Pathology, University College London Medical School, University Street, London WC1E 6JJ, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Oxford Centre for Cancer Gene Research, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Translational Cancer Therapeutics Laboratory, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC2E 6DD, UK. Electronic address: charles.swanton@crick.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology; D053143:Caspase 2 / Q000032:analysis / Q000502:physiology*; D020090:Chromosome Segregation; D015179:Colorectal Neoplasms / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000032:analysis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C495498:BCL9L protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases
keywords: BCL9L; BID; aneuploidy tolerance; caspase-2; chromosomal instability; chromosome segregation errors; colorectal cancer evolution; intratumor heterogeneity; mitotic checkpoint; p53