TY - JOUR
T1 - BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer
AU - López-García, Carlos
AU - Sansregret, Laurent
AU - Domingo, Enric
AU - McGranahan, Nicholas
AU - Hobor, Sebastijan
AU - Birkbak, Nicolai Juul
AU - Horswell, Stuart
AU - Grönroos, Eva
AU - Favero, Francesco
AU - Rowan, Andrew J.
AU - Matthews, Nicholas
AU - Begum, Sharmin
AU - Phillimore, Benjamin
AU - Burrell, Rebecca
AU - Oukrif, Dahmane
AU - Spencer-Dene, Bradley
AU - Kovac, Michal
AU - Stamp, Gordon
AU - Stewart, Aengus
AU - Danielsen, Havard
AU - Novelli, Marco
AU - Tomlinson, Ian
AU - Swanton, Charles
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - aneuploidy tolerance
KW - chromosomal instability
KW - BCL9L
KW - caspase-2
KW - p53
KW - intratumor heterogeneity
KW - chromosome segregation errors
KW - mitotic checkpoint
KW - BID
KW - colorectal cancer evolution
U2 - 10.1016/j.ccell.2016.11.001
DO - 10.1016/j.ccell.2016.11.001
M3 - Journal article
C2 - 28073006
SN - 1535-6108
VL - 31
SP - 79
EP - 93
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
