期刊
NATURE
卷 587, 期 7832, 页码 126-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2698-6
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资金
- Francis Crick Institute from Cancer Research UK [FC001169, FC010110, FC001202]
- UK Medical Research Council [FC001169, FC010110, FC001202]
- Wellcome Trust [FC001169, FC010110, FC001202, 211179/Z/18/Z]
- Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013) [607722]
- Breast Cancer Research Foundation (BCRF)
- Royal Society Research Professorships Enhancement Award [RP/EA/180007]
- Foulkes Foundation
- NovoNordisk Foundation [ID 16584]
- Aarhus University Research Foundation
- European Research Council [FP7-THESEUS-617844, PROTEUS-835297]
- European Union's Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant [703594-DECODE]
- UK Medical Research Council Skills Development Fellowship Award [MR/P014712/1]
- Wellcome Trust Clinical Career Development Fellowship [214584/Z/18/Z]
- CRUK Early Detection Pump Prime Award
- NCI Outstanding Investigatory Award [1R35CA220481]
- Swedish Cancer Society
- Swedish Research Council
- Berta Kamprad Foundation
- National Breast Cancer Foundation of Australia Endowed Chair
- Breast Cancer Research Foundation, New York
- Cancer Research UK [C50947/A18176]
- National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden Hospital and Institute of Cancer Research [A109]
- Kidney and Melanoma Cancer Fund of The Royal Marsden Cancer Charity
- The Rosetrees Trust [A2204]
- National Institute for Health Research
- Rosetrees Trust
- UKI NETs
- NIHR University College London Hospitals Biomedical Research Centre
- Office of the Director, the National Institutes of Health [DP5OD026395]
- Department of Defense Breast Cancer Research Breakthrough Award [W81XWH-16-1-0315, BC151244]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Parker Institute for Immunotherapy at MSKCC
- Josie Robertson Foundation
- MSKCC core grant [P30-CA008748]
- Helmholtz Association (Germany)
- Royal Society [211179/Z/18/Z]
- NIHR BRC at University College London Hospitals
- CRUK University College London Experimental Cancer Medicine Centre
- Cancer Research UK (TRACERx)
- Cancer Research UK (PEACE)
- Cancer Research UK (CRUK Cancer Immunotherapy Catalyst Network)
- Cancer Research UK Lung Cancer Centre of Excellence
- Butterfield Trust
- Stoneygate Trust
- CRUK-UCL Centre, Experimental Cancer Medicine Centre
- Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant [SU2C-AACR-DT23-17]
- Stand Up To Cancer is a program of the Entertainment Industry Foundation
- American Association for Cancer Research
- Scientific Partner of SU2C
- European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013) Consolidator Grant [FP7-THESEUS-617844]
- European Commission ITN FP7-PloidyNet [607722]
- ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation programme [835297]
- Chromavision from the European Union's Horizon 2020 research and innovation programme [665233]
- Medical Research Council [MR/L016311/1]
- High-Performance Computing at the Francis Crick Institute
- UCL Department of Computer Science Cluster
- Medical Research Council [MR/L016311/1] Funding Source: researchfish
- MRC [MR/P014712/1, MR/L016311/1] Funding Source: UKRI
- Wellcome Trust [214584/Z/18/Z] Funding Source: Wellcome Trust
Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes(1,2). The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution(1,3,4). Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompassesBCL9, MCL1andARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) in HER2(+)breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution. Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.
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