Editors' ChoiceCancer

Catastrophe in the Nucleus

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Science Translational Medicine  19 Jan 2011:
Vol. 3, Issue 66, pp. 66ec9
DOI: 10.1126/scitranslmed.3002126

The initial sequencing of the human genome led to an avalanche of progress and data. Cancer, as a disease driven by mutations, continues to be the focus of genomic efforts. Early technology was limited to the identification of sequence changes, such as point mutations, in cancer cells. However, two types of changes were not seen by simple sequencing: copy number variations and gene rearrangements, both of which require specialized techniques to observe. Such analyses brought many surprises, such as the finding that gene rearrangements—previously well-described in only a handful of cancers, such as chronic myelogenous leukemia or Ewing sarcoma—are present, often in large numbers, in most solid tumor specimens.

Another surprise is the subject of a recent study published by Campbell and colleagues. They found that in about 2 to 3% of cancers, and up to 25% of osteosarcomas, the gene rearrangements and copy number variants are confined to one region of a single chromosome. Detailed analysis of such regions suggests that they arise through a single catastrophic event, during which the chromosome region is shattered into small fragments that are stitched back together in the wrong order by the cell’s repair machinery. The authors name this phenomenon "chromothripsis" (Greek for “chromosome shattering”). Although usually such an event would lead to apoptosis, rare cells that survive may go on to form tumors. The authors demonstrate that in some cases, oncogenes may be turned on, and tumor suppressors inactivated, through a single chromothripsis event rather than through a sequential multi-step process that has become the dogma of cancer biology.

The cause of such an event remains unknown, but the authors propose two provocative models. According to one, a single “hit” by a pulse of ionizing radiation when the chromosomes are condensed for mitosis might lead to localized fragmentation. Another model suggests a role for telomere attrition. The findings demonstrate again that cancer is a skilled enemy, but give us hope that understanding the anatomy of its abnormal genome will enable us to overpower this deadly disease.

P. J. Stephens et al., Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). [Full Text]

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