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Many Copy Number Variations Universal Among Diverse Tumors

An international team of researchers has created a genome-scale map of 26 different cancers, revealing more than 100 genomic sites where DNA from tumors is either missing or abnormally duplicated compared to normal tissues. The study, the largest of its kind, finds that most of these genetic abnormalities are not unique to one form of cancer, but are shared across multiple cancers. "Our findings show that many genome alterations are universal across different cancers. Although this has been known for some types of changes, the degree to which so many alterations are shared was pretty surprising to us," said senior author Dr. Matthew Meyerson, a professor of pathology at the Dana-Farber Cancer Institute and senior associate member of the Broad Institute of Harvard and MIT. "It suggests that, in the future, a driving force behind cancer treatment will be common genomic alterations, rather than tumors' tissue of origin." In 2004, a scientific team led by researchers at the Dana-Farber Cancer Institute and the Broad Institute launched a project to systematically map genetic changes across different cancers. They focused on a particular type of DNA change in which segments of a tumor's genome are present in abnormal numbers of copies. Instead of the usual two copies, tumors often carry several copies of one piece of DNA (an "amplification") or may lack it altogether (a "deletion"). These genetic abnormalities are known as somatic copy-number alterations or SCNAs. As the foundation for their analysis, the scientists collected over 2,500 cancer specimens representing more than two dozen cancer types, including lung, prostate, breast, ovarian, colon, esophageal, liver, brain, and blood cancers.

Using powerful genomic "chip" technologies, the researchers analyzed DNA from these samples, and combined their data with publicly available data from another 600 tumor samples to assemble a detailed catalogue of the SCNAs present in multiple tumor types. They found that the most common SCNAs tended to come in two sizes: relatively long, about the length of an entire chromosome or a single chromosome arm; and short, with an average size of about 1.8 million bases or 0.03% of the entire human genome.

The researchers focused their attention on the short, or focal, SCNAs, which, due to their relatively compact size, could facilitate the task of pinpointing important cancer genes.

Of the approximately 150 focal SCNAs they identified, Meyerson and his colleagues noticed that the majority did not coincide with genes already known to be amplified or deleted in cancer. Looking more closely at the genes that normally reside in these regions, the researchers found an enrichment of genes with important biological functions in cancer, such as programmed cell death (or "apoptosis").

This analysis also helped shed light on two genes, MCL1 and BCL2L1. Cancer cells with amplifications of these genes appear to rely on the genes' activity for survival, suggesting important roles in maintaining tumor growth.

Perhaps most importantly, looking across the data for the various cancers, it became clear that most focal SCNAs are not unique to just one type of cancer, but are shared among multiple tumor types. In an analysis of 17 different cancer types, the researchers found that a majority of amplifications and deletions are present in more than one type.

That suggests the genetic mechanisms that underlie these tumors are shared among them, and could someday lead to common strategies for treating them.
"These data signify an important resource for cancer gene discovery, but they're only a first step," said Dr. Meyerson. "With the ongoing revolution in genome technology, it will become possible to decode the genomes of thousands of cancers to reveal every genomic change."

This work was reported in the February 18, 2010 issue of Nature. [Press release] [Nature abstract]