Scientific Method / Science & Exploration

Copy number changes point to new cancer genes

A study that looks at changes in gene dose in cancer cells finds some new …

With the human genome complete, one of the more prominent follow-up projects has been the cancer genome, in which researchers attempted to study the complete catalog of mutations that are present in different cancers. So far, the results have been pretty mixed, with mutations in a lot of genes we already knew about, and many indications that cancers from different tissues have distinct collections of mutations. All of these are present against a massive background of DNA base changes that might be significant to the disease, or irrelevant. But two new studies indicate that, for large DNA differences, it might be possible to separate out informative changes.

The challenge with studying cancer-causing mutations is that, as part of the progression of the disease, cells tend to accumulate damage to the proteins that keep them dividing in a healthy and controlled fashion. As a result, the pathways that keep cells with DNA damage from dividing tend to get inactivated, so cancer cells pick up many additional mutations, some relevant to the disease, others not. Determining whether a mutation is a contributor to the disease or a harmless passenger has always been challenging.

If anything, the challenge has gotten more difficult in the era of genome sequencing, as evidenced by some of the first results of the cancer genome project. It has been easy to generate huge lists of mutations from DNA sequencing, but many turned out to be errors, irrelevant, or specific to a single type of cancer.

The two papers, released today by Nature, take a different approach. Instead of performing DNA sequencing, which can identify changes in individual bases, they look for copy number variations, in which larger segments of DNA are either duplicated or deleted. CNVs can include one or more entire genes, and the change in gene dose can alter the amount of RNA and protein produced, with significant biological consequences.

The problem, as with base mutations, is that CNVs also tend to become more common in cancer cells; in fact, one of the studies found that extra or missing copies of entire chromosome arms were among the most common CNVs present. The advantage of the approach is that it's much easier to look for CNVs than it is to sequence an entire genome, meaning that the researchers were able to work through many more samples, and obtain higher degrees of statistical significance.

In one paper, the authors looked at both duplications and deletions in a total of over 3,000 cancer cell lines, representing 26 distinct types of cancer. Those numbers allowed the areas of the genome that are consistently altered in many types of cancer to rise out of the statistical noise caused by the general DNA damage. In the second paper, the authors looked exclusively at deleted regions of DNA using about 750 different cancer cell lines. They were able to perform a statistical analysis that separated areas prone to DNA rearrangements from areas that appeared to undergo selection for changes specifically in cancer cell lines.

The good news is that there seem to be a number of new genes implicated in the progression of cancer by these studies. The latter paper successfully identified rearrangements that deleted a number of known cancer genes, such as SMAD4 and PTEN, but also came up with a series of about a dozen common deletions that don't contain anything obvious.

The larger study, which included both deletions and duplications, did even better. It picked up a total of 158 independent DNA rearrangements. Some of these included expected genes, like MYC and ERB B2, but many didn't have any genes that had been directly implicated in cancer. These tended to contain genes of the sort we would suspect to be involved in cancer, though—regulators of the cell cycle, kinases, etc. Many of the genes were involved with the NF-kappa B signaling pathway, which regulates immune function and inflammation; others regulate apoptosis, a process by which aberrant cells can be induced to die. The authors of the paper validated that two of the new apoptotic regulators are involved in cancer by knocking the genes down using RNA interference.

The good news here is that, in contrast to some sequencing studies, many of the CNVs were implicated in a variety of cancer cell types, rather than being specific for cancers derived from a single tissue: "By studying a large number of cancers of multiple types, we have found that most of the significant [CNVs] within any single cancer type tend to be found in other cancer types as well." The other good news is that these common CNVs appear to be identifying new genes on known pathways implicated in cancer.

The authors of the latter paper have also made their data available to the public at the Broad Institute website.

Nature, 2010. DOI: 10.1038/nature08822
Nature, 2010. DOI: 10.1038/nature08768

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