Clonal Evolution

Chromothripsis

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Chromothripsis

Definition

Chromothripsis (from Greek chromo- for chromosome and thripsis, shattering into pieces) is a catastrophic mutational process in which many clustered structural variants arise in a single event, often affecting one or a few chromosomes. First described by Stephens et al. (2011), it is the genomic signature of a one-off cellular crisis — tens to hundreds of rearrangements concentrated in localized genomic regions — rather than gradual accumulation of structural variants over time.

Pan-Cancer Frequency

The PCAWG Consortium (2020) identified chromothripsis in 587 of 2,583 samples (22.3%), making it a common event across cancer types. Highest frequencies were observed in sarcoma, glioblastoma, lung squamous cell carcinoma, melanoma, and breast adenocarcinoma. Chromothripsis was associated with whole-genome-duplication in most cancer types.

Patterns Across Cancer Types

Chromothripsis manifests in cancer-type-specific patterns (PCAWG Consortium, 2020):

  • Liposarcoma: events often involve multiple chromosomes, with universal MDM2 amplification and co-amplification of TERT in select cases
  • Glioblastoma: focal events on a single chromosome, distant from telomeres, resulting in EGFR and MDM2 amplification with CDKN2A loss
  • Acral melanoma: frequent CCND1 amplification; chromothripsis typically precedes most somatic point mutations
  • Lung squamous cell carcinoma: SOX2 amplification; later event in evolution (many amplified SNVs)
  • Chromophobe RCC: events predominantly on chromosome 5, with breakpoints adjacent to TERT, increasing TERT expression ~80-fold

Evolutionary Timing

Chromothripsis tends to be an early event in tumour evolution. PCAWG Consortium (2020) showed that chromothripsis had greater relative odds of being clonal than subclonal, indicating it typically occurs before the emergence of the most recent common ancestor of the tumour cell population. In acral melanoma, chromothripsis events precede most somatic point mutations, affecting several cancer-associated genes simultaneously.

Enrichment for Drivers

Chromothripsis regions coincided with 3.6% of all identified drivers in PCAWG and approximately 7% of copy-number drivers — significantly enriched beyond the expectation if selection were not acting on these events (PCAWG Consortium, 2020). The majority of coinciding driver events were amplifications (58%), followed by homozygous deletions (34%) and structural variants within genes or promoter regions (8%). TP53 was the most recurrently associated driver (pan-cancer odds ratio = 3.22).

Significance for Clonal Evolution

Chromothripsis represents a mechanism of punctuated-evolution — a saltatory genotype change that can simultaneously alter multiple cancer genes, producing a large fitness jump in a single event rather than incremental adaptation. Its predominantly early, clonal timing means it can be a founding event in tumour evolution, establishing the genomic landscape upon which subsequent gradual evolution operates. The cancer-type-specific patterns suggest that the selective value of chromothripsis depends on tissue context — the same catastrophic process produces different driver combinations in different tissues.

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