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Sequencing Study Suggests Single Large Rearrangement Events Underlie Some Cancers

By Andrea Anderson

NEW YORK (GenomeWeb News) – Cancer causing chromosomal rearrangements don't always build up over time, but can sometimes occur in one fell swoop, according to a paper appearing online today in Cell.

Using high-throughput sequencing and microarrays, researchers from the UK and the US found evidence that a fraction of cancers spawn from cells that have succumbed to sudden genomic reorganizations involving between a few dozen and several hundred rearrangements, a phenomenon that they dubbed "chromothripsis." Results from the team's analyses of hundreds of cancer cell lines indicate that somewhere in the neighborhood of two to three percent of all cancers — and about a quarter of bone cancers — involve chromothripsis.

While some cells with catastrophic chromosomal damage undergo apoptosis and die, corresponding author Peter Campbell, a researcher affiliated with the Wellcome Trust Sanger Institute's Cancer Genome Project, the University of Cambridge, and Addenbrooke's Hospital, told GenomeWeb Daily News, others can stitch together an "alphabet soup of chromosomal fragments" and then go on to not only survive, but to gain a selective advantage that ultimately leads to cancer.

Past research has shown that many of the point mutations and chromosomal rearrangements that convert normal somatic cells to cancerous cells take years or even decades to develop, the researchers explained, often transitioning through one or more distinct pre-cancerous stages.

"The prevailing dogma of cancer evolution is … one of 'gradualism' in which acquisition of driver mutations occurs cumulatively over years to decades, resulting in incremental progression through increasingly malignant phenotypes," they wrote.

While that may be the case for most cancers, Campbell explained, the new findings suggest some cells undergo rearrangements that dramatically reshape parts of their genomes in short order — consistent with the apparent rapidity with which cancer appears in some cases.

"We do know that some cancers appear to develop much more quickly," Campbell noted. "It may well be that cancers can develop more quickly than the standard model of development over decades."

The revelation stemmed from the team's efforts to characterize rearrangements in a type of leukemia known as chronic B cell lymphocytic leukemia.

Using the Illumina Genome Analyzer II, the researchers did massively parallel, paired-end sequencing to look for chromosomal rearrangements in 10 CLL samples collected from as many different individuals at Addenbrooke's Hospital in the UK.

One of these individuals not only carried a smattering of focal point changes and rearrangements on chromosomes 1, 12, 13, and 15, but also a cluster of 42 rearrangements concentrated on one arm of chromosome 4, the team noted — a pattern that was strikingly different from the genome-wide changes previously reported for breast, lung, and pancreatic cancers.

When the team used Affymetrix SNP6 arrays to assess 746 cancer cell lines, they discovered that around two to three percent of the cancers tested showed evidence of chromothripsis — findings that they verified through more in-depth sequencing studies of four lines representing colorectal, thyroid, renal, and small cell lung cancer samples.

Such changes were even more common in the 20 bone cancer samples, they found, turning up in a quarter of the samples tested.

Given the patterns detected, the team argues that it is extremely unlikely that these genetic changes accumulated in the cells over time. Instead, the nature and localization of these rearrangements point to rapid rearrangements in the genome.

While much of the genome is "quite quiet" in cells that have undergone chromothripsis, Campbell explained, these cells typically have one chromosome, chromosomal arm, or region of a chromosome that is radically rearranged.

"Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis," the researchers explained. "Rearrangements involving one or a few chromosomes criss-cross back and forth across involved regions."

Although they emphasized that more research is needed to figure the cause of chromothripsis, the researchers speculated that it might be a consequence of exposure to ionizing radiation and/or other environmental exposures.

To explore this possibility, Campbell explained, the team eventually hopes to characterize tumors that have been exposed to therapeutic radiation as well as cancers that appear to have been caused by exposure to environmental radiation.

The researchers are also trying to induce chromothripsis in vitro in an effort to learn more about how it occurs in the body, he noted.

"Whatever the mechanism of damage, the consequences are profound," the team concluded. "Faced with hundreds of DNA breaks, the cell's DNA repair machinery attempts to rescue the genome. The resultant hodgepodge bears little resemblance to its original structure, and the genomic disruption has wholesale and potentially oncogenic effects."