Pervasive chromosomal instability and karyotype order in tumour evolution

Thomas B. K. Watkins, Emilia L. Lim, Marina Petkovic, Sergi Elizalde, Nicolai J. Birkbak, Gareth A. Wilson, David A. Moore, Eva Gronroos, 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 LitchfieldWei 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, Cecile Vicier, Ian P. M. Tomlinson, Priscilla K. Brastianos, Raymond J. Cho, Boris C. Bastian, Lars Dyrskjot, Goran B. Jonsson, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

80 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)126-132
JournalNature
Volume587
Issue number7832
Early online date2 Sep 2020
DOIs
Publication statusPublished - 5 Nov 2020

Keywords

  • CANCER
  • METASTASIS
  • IDENTIFICATION
  • EXPRESSION
  • PATTERNS
  • GENES
  • MODEL

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