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

被引：83

作者：

Lopez-Garcia, Carlos ^{[1
]}

Sansregret, Laurent ^{[1
]}

Domingo, Enric ^{[5
,6
]}

McGranahan, Nicholas ^{[1
,7
]}

Hobor, Sebastijan ^{[1
]}

Birkbak, Nicolai Juul ^{[1
,7
]}

Horswell, Stuart ^{[2
]}

Gronroos, Eva ^{[1
]}

Favero, Francesco ^{[1
,8
]}

Rowan, Andrew J. ^{[1
]}

Matthews, Nicholas ^{[4
]}

Begum, Sharmin ^{[4
]}

Phillimore, Benjamin ^{[4
]}

Burrell, Rebecca ^{[1
]}

Oukrif, Dahmane ^{[9
]}

Spencer-Dene, Bradley ^{[3
]}

Kovac, Michal ^{[5
]}

Stamp, Gordon ^{[3
]}

Stewart, Aengus ^{[2
]}

Danielsen, Havard ^{[10
]}

Novelli, Marco ^{[9
]}

Tomlinson, Ian ^{[5
]}

Swanton, Charles ^{[1
,7
]}

机构：

[1] Francis Crick Inst, Translat Canc Therapeut Lab, 1 Midland Rd, London NW1 1AT, England

[2] Francis Crick Inst, Bioinformat Sci Technol Platform, 1 Midland Rd, London NW1 1AT, England

[3] Francis Crick Inst, Expt Histopathol Lab, 1 Midland Rd, London NW1 1AT, England

[4] Francis Crick Inst, Adv Sequencing Facil, 1 Midland Rd, London NW1 1AT, England

[5] Wellcome Trust Ctr Human Genet, Oxford Ctr Canc Gene Res, Roosevelt Dr, Oxford OX3 7BN, England

[6] Univ Oxford, Dept Oncol, Roosevelt Dr, Oxford OX3 7DQ, England

[7] UCL, Translat Canc Therapeut Lab, Inst Canc, Paul OGorman Bldg,72 Huntley St, London WC2E 6DD, England

[8] Tech Univ Denmark, Dept Syst Biol, Canc Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark

[9] UCL, Dept Pathol Res, Sch Med, Univ St, London WC1E 6JJ, England

[10] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Genet & Informat, Ullernchausseen 70, N-0379 Oslo, Norway

来源：

CANCER CELL | 2017年 / 31卷 / 01期

基金：

欧洲研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

CHROMOSOMAL INSTABILITY; MICROSATELLITE INSTABILITY; GENOMIC HETEROGENEITY; DNA-DAMAGE; MUTATIONS; ERRORS; IDENTIFICATION; HYBRIDIZATION; TUMORIGENESIS; SEGREGATION;

D O I：

10.1016/j.ccell.2016.11.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：79 / 93

页数：15

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