López-García Carlos, Sansregret Laurent, Domingo Enric, McGranahan Nicholas, Hobor Sebastijan, Birkbak Nicolai Juul, Horswell Stuart, Grönroos Eva, Favero Francesco, Rowan Andrew J, Matthews Nicholas, Begum Sharmin, Phillimore Benjamin, Burrell Rebecca, Oukrif Dahmane, Spencer-Dene Bradley, Kovac Michal, Stamp Gordon, Stewart Aengus, Danielsen Havard, Novelli Marco, Tomlinson Ian, Swanton Charles
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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.
Cancer Cell. 2017 Jan 9;31(1):79-93. doi: 10.1016/j.ccell.2016.11.001.
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.
染色体不稳定性（CIN）促进癌症进展、肿瘤内异质性和耐药性。CIN由染色体分离错误和允许非整倍体基因组增殖的耐受表型驱动。通过对结直肠癌和细胞系的基因组分析，我们发现在非整倍体肿瘤中BCL9L频繁发生杂合性缺失和突变。BCL9L缺陷可能通过调节Wnt信号通路，促进了异种移植模型中染色体错分离事件的耐受性、非整倍体增殖和遗传异质性。我们发现，BCL9L功能障碍通过降低基础caspase-2水平并阻止MDM2和BID的裂解，导致TP53野生型和突变型细胞对非整倍体的耐受性。利用非整倍体耐受机制和BCL9L/caspase-2/BID轴的研究可能会限制癌症的多样性和进展。
