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Copy Number Studies Point to Gains, Losses, and Driver Mutations in Cancers

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a pair of papers appearing online in Nature today, two research teams have used copy number analyses to gain insights into the genomic features of cancer.

In the first of these, researchers from the Wellcome Trust Sanger Institute, Michigan's Van Andel Institute, and the Institute of Cancer Research in Surrey used microarray-based experiments and targeted sequencing to identify signatures of selection and mutation in nearly 750 cancer cell lines.

They found 2,428 somatic homozygous deletions, including deletions affecting tumor suppressor genes as well as deletions occurring at so-called "fragile sites" in the genome. By exploiting structural signatures in the genome, the team was able to tease apart deletions involving cancer genes from those at fragile sites.

"Our study provides one example of how researchers can sift through the large numbers of a particular type of mutation present in cancer genomes in order to distinguish drivers from passengers," senior author Michael Stratton, a researcher with the Sanger Institute and Institute of Cancer Research, said in a statement.

To do this, the researchers used Affymetrix SNP 6.0 arrays to genotype and find copy number changes in 746 publicly available cancer cell lines, mapping breakpoints coinciding with the edges of amplifications and deletions and losses of heterozygosity.

They then surveyed the locations of homozygous deletions, integrated this data with sequence and expression information on dozens of known cancer genes, and came up with structural signatures for differentiating between cancer gene deletions and deletions at fragile sites.

"The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes," the researchers explained. "The extensive copy number, genotyping, sequence, and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery."

Meanwhile, Matthew Meyerson, a researcher affiliated with the Broad Institute, the Dana-Farber Cancer Institute, and Harvard Medical School, led a team of researchers who looked at more than two dozen cancers, mapping the copy number changes within the cancer genomes. In the process, they found an unexpectedly high amount of overlap between copy number changes in various kinds of cancer.

"Our findings show that many genome alterations are universal across different cancers," Meyerson said in a statement. "Although this has been known for some types of changes, the degree to which so many alterations are shared was pretty surprising to us."

He and his colleagues used the Affymetrix 250 K Sty array to assess 2,509 cancer samples. They then combined this with publicly available data on another 622 samples. Together, these 3,131 samples represented 26 cancer types.

When the team compared copy number profiles in the cancer samples with those in nearly 1,500 normal tissue samples, they turned up 75,500 gains and 55,101 losses in the cancer genomes.

Many of these somatic copy number changes affected known tumor suppressor genes or genes involved in cell cycle related pathways. Still, they noted, genes involved in apoptosis were also well represented.

And numerous copy number alterations overlapped between different cancer types. That suggests that it may eventually be possible to glean insights from the pattern of genomic alterations in a tumor rather than just where it originates in the body, Meyerson said, noting that the copy number patterns may provide clues about how to treat cancers.

"These data signify an important resource for cancer gene discovery, but they're only a first step," Meyerson said in a statement. "With the ongoing revolution in genome technology, it will become possible to decode the genomes of thousands of cancers to reveal every genomic change."

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