小柯机器人

英国弗朗西斯·克里克研究所Charles Swanton研究小组，揭示了肿瘤发展过程中普遍存在的染色体不稳定性和核型顺序。相关论文于2020年9月2日在线发表在《自然》杂志上。

研究人员对来自22种肿瘤类型394个肿瘤的1,421个样本进行了多样本定相和体细胞拷贝数改变（SCNA）分析，以揭示连续染色体不稳定性导致的SCNA异质性。在单一亚克隆中，引起相同基因（例如BCL9、MCL1、ARNT（也称为HIF1B）、TERT和MYC）破坏的平行进化发生在37％的肿瘤中。大多数复发性丢失可能发生在全基因组加倍之前，这是在49％的肿瘤中观察到的克隆事件。

然而，即使在全基因组加倍的肿瘤中，大量亚克隆会发生人白细胞抗原（HLA）基因座杂合性缺失和染色体8p丢失至单个单倍体拷贝，这表明核型正发生重塑。影响染色体1q21（包括BCL9、MCL1和ARNT）、5p15.33（TERT）、11q13.3（CCND1）、19q12（CCNE1）和8q24.1（MYC）的焦点扩增通常是由亚克隆造成的，但只发生在单个样本中。研究人员对1,024个独立转移性样本进行分析后发现转移性样本中存在13个局灶性SCNA，包括肾透明细胞癌8q24.1染色体（包含MYC）和HER2⁺乳腺癌的11q13.3染色体（包含CCND1）。 染色体不稳定性可能导致SCNA的连续性选择，SCNA被认为是在整个肿瘤进化过程中发生的并行事件。

据悉，在癌症中染色体不稳定包括对染色体数目和结构的动态改变。SCNA产生的多样性结果可能为肿瘤发展提供必要的变异。

附：英文原文

Title: Pervasive chromosomal instability and karyotype order in tumour evolution

Author: Thomas B. K. Watkins, Emilia L. Lim, Marina Petkovic, Sergi Elizalde, Nicolai J. Birkbak, Gareth A. Wilson, David A. Moore, Eva Grnroos, Andrew Rowan, Sally M. Dewhurst, Jonas Demeulemeester, Stefan C. Dentro, Stuart Horswell, Lewis Au, Kerstin Haase, Mickael Escudero, Rachel Rosenthal, Maise Al Bakir, Hang Xu, Kevin Litchfield, Wei Ting Lu, Thanos P. Mourikis, Michelle Dietzen, Lavinia Spain, George D. Cresswell, Dhruva Biswas, Philippe Lamy, Iver Nordentoft, Katja Harbst, Francesc Castro-Giner, Lucy R. Yates, Franco Caramia, Fanny Jaulin, Ccile Vicier, Ian P. M. Tomlinson, Priscilla K. Brastianos, Raymond J. Cho, Boris C. Bastian, Lars Dyrskjt, Gran B. Jnsson, Peter Savas, Sherene Loi, Peter J. Campbell, Fabrice Andre, Nicholas M. Luscombe, Neeltje Steeghs, Vivianne C. G. Tjan-Heijnen, Zoltan Szallasi, Samra Turajlic, Mariam Jamal-Hanjani, Peter Van Loo, Samuel F. Bakhoum, Roland F. Schwarz, Nicholas McGranahan, Charles Swanton

Issue&Volume: 2020-09-02

Abstract: Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. 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.

DOI: 10.1038/s41586-020-2698-6

Source: https://www.nature.com/articles/s41586-020-2698-6

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