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.
