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Pervasive chromosomal instability and karyotype order in tumour evolution
Nature ( IF 50.5 ) Pub Date : 2020-09-02 , DOI: 10.1038/s41586-020-2698-6
Thomas B K Watkins 1 , Emilia L Lim 1, 2 , Marina Petkovic 3 , Sergi Elizalde 4 , Nicolai J Birkbak 1, 5, 6 , Gareth A Wilson 1 , David A Moore 2, 7 , Eva Grönroos 1 , Andrew Rowan 1 , Sally M Dewhurst 8 , Jonas Demeulemeester 9, 10 , Stefan C Dentro 9, 11, 12 , Stuart Horswell 13 , Lewis Au 14, 15 , Kerstin Haase 9 , Mickael Escudero 13 , Rachel Rosenthal 1, 2, 16 , Maise Al Bakir 1 , Hang Xu 17 , Kevin Litchfield 1 , Wei Ting Lu 1 , Thanos P Mourikis 2, 18 , Michelle Dietzen 2, 18 , Lavinia Spain 14, 15 , George D Cresswell 19 , Dhruva Biswas 1, 16 , Philippe Lamy 5 , Iver Nordentoft 5 , Katja Harbst 20, 21 , Francesc Castro-Giner 22, 23 , Lucy R Yates 24, 25 , Franco Caramia 26 , Fanny Jaulin 27 , Cécile Vicier 28 , Ian P M Tomlinson 29 , Priscilla K Brastianos 30, 31, 32 , Raymond J Cho 33 , Boris C Bastian 33, 34, 35 , Lars Dyrskjøt 5 , Göran B Jönsson 20, 21 , Peter Savas 26, 36 , Sherene Loi 26, 36 , Peter J Campbell 24 , Fabrice Andre 37, 38, 39 , Nicholas M Luscombe 19, 40, 41 , Neeltje Steeghs 42 , Vivianne C G Tjan-Heijnen 43 , Zoltan Szallasi 44, 45, 46 , Samra Turajlic 14, 15 , Mariam Jamal-Hanjani 2, 47 , Peter Van Loo 9 , Samuel F Bakhoum 48, 49 , Roland F Schwarz 3, 50, 51 , Nicholas McGranahan 2, 18 , Charles Swanton 1, 2, 47
Affiliation  

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 as BCL9 , MCL1 , ARNT (also known as HIF1B ), TERT and MYC ) 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 encompasses BCL9, MCL1 and ARNT ), 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 (encompassing MYC ) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1 ) 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.

中文翻译:


肿瘤进化中普遍存在的染色体不稳定性和核型顺序



癌症中的染色体不稳定性包括 1、2 号染色体数量和结构的动态变化。由此产生的体细胞拷贝数改变 (SCNA) 的多样性可能提供肿瘤进化所需的变异 1 , 3 , 4 。在这里,我们对来自 22 种肿瘤类型的 394 个肿瘤的 1,421 个样本进行多样本定相和 SCNA 分析,以表明持续的染色体不稳定性导致普遍的 SCNA 异质性。 37% 的肿瘤中存在平行进化事件,这些事件会导致不同亚克隆内的相同基因(例如 BCL9、MCL1、ARNT(也称为 HIF1B)、TERT 和 MYC)遭到破坏。大多数复发性丢失可能发生在全基因组加倍之前,在 49% 的肿瘤中发现全基因组加倍是克隆事件。然而,人类白细胞抗原(HLA)基因座杂合性的丧失和 8p 染色体丢失为单个单倍体副本的情况以相当大的亚克隆频率重复出现,甚至在全基因组加倍的肿瘤中也是如此,这表明正在进行的核型重塑。影响染色体 1q21(包括 BCL9、MCL1 和 ARNT)、5p15.33(TERT)、11q13.3(CCND1)、19q12(CCNE1)和 8q24.1(MYC)的局部扩增经常是亚克隆,但似乎是克隆内单个样品。对 1,024 个转移样本的独立系列分析显示,转移样本中富集了 13 个局灶性 SCNA,包括透明细胞肾细胞癌中染色体 8q24.1(包含 MYC)和 HER2 + 乳腺癌中染色体 11q13.3(包含 CCND1)的增加癌症。染色体不稳定性可能使得 SCNA 能够连续选择,这些 SCNA 被确定为在整个肿瘤进化过程中经常并行发生的有序事件。 染色体不稳定性使得体细胞拷贝数改变的连续选择成为可能,这些改变被确定为在整个肿瘤进化和转移过程中经常并行发生的有序事件。
更新日期:2020-09-02
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