Abstract
Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.
Highlights
Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s)
Tumour and matched germline samples were processed with standardized pipelines to detect single nucleotide variants (SNVs), short insertions and deletions, copynumber variants (CNVs) and other structural variants
We examined a second group of patients belonging to the same cohort but analysed independently, for which we scored chromothripsis based on whole-exome sequences (n = 318), making use of the off-target reads to maximize the resolution of the CNV calling
Summary
Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). The development of next-generation sequencing technologies and their applications in cancer genome studies have enabled the discovery of a new form of genome instability called chromothripsis[1,2]. This catastrophic process drastically contrasts with the classical view of multi-step tumour evolution. Cai and colleagues performed a comprehensive analysis of chromothriptic-like patterns in large SNP array and comparative genomic hybridization datasets[13] This type of data, even though available for large cohorts, does not allow formal testing of all criteria defining chromothripsis for a conclusive identification of bona fide chromothriptic cases[3]. We detect a surprisingly high frequency of chromothriptic events and identify marked differences in genomic features between tumours with or without chromothripsis
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