Abstract
BackgroundChromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a “one-off” catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood.ResultsHere, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate.ConclusionsThrough a large-scale analysis of oncogenomic array data sets, this study characterized features associated with genomic aberrations patterns, compatible to the spectrum of “chromothripsis”-definitions as previously used. While quantifying clustered genomic copy number aberrations in cancer samples, our data indicates an underlying biological heterogeneity behind these chromothripsis-like patterns, beyond a well defined “chromthripsis” phenomenon.
Highlights
Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event
Chromothripsis-like patterns across diverse tumor types When evaluating the 1,269 chromothripsis-like patterns (CTLP) events, we found a pronounced preference for some chromosomes; this preference showed only limited association with chromosome size (Figure 2A)
To test whether CTLP generating events are associated with overall genomic instability, we examined the extent of all copy number imbalances detected in our dataset
Summary
Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a “one-off” catastrophic event. Using state-of-the-art genome analysis techniques, a phenomenon termed “chromothripsis” was characterized in cancer genomes, defined by the occurrence of tens to hundreds of clustered genomic rearrangements, having arisen in a single catastrophic event [9]. In this model, contiguous chromosomal regions are fragmented into many pieces, via presently unknown mechanisms. The initial study reported 24 chromothripsis cases, with some evidence of a high prevalence in bone tumors [9]
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