Identifying Spurious Cancer Mutations

Researchers reveal why analyses of cancer-causing mutations are riddled with false positives and demonstrate a new approach that eliminates the problem.

By | June 19, 2013

ISTOCK, ALENGOAnalyses of cancer genome data turn up many highly mutated genes that appear to be associated with the disease, but a hefty portion of those are red herrings. These false positives are the result of naturally varying rates of mutation across the genome, according to a study published yesterday (June 18) in Nature. The authors also demonstrate a new analytical approach that helps cancer researchers focus on relevant genes.

Mutations occur in all cells, but the genomes of cancer cells accumulate more errors than most, largely because tumor cells proliferate faster than healthy cells. Conventional approaches to identifying mutations that drive the disease involve the analysis of tumor genomes to see which mutations occur more frequently than expected by random chance. As the number of sequenced cancer genomes rises, the list of seemingly significant genes has grown ever longer.

But mutation rates are not naturally uniform across the whole genome, realized a team led by study author Gad Getz, computational biologist at the Broad Institute in Cambridge, Massachusetts. Indeed, some genes are more prone to accumulating mutations than others. “Not taking these highly mutable genetic regions into account leads to declaring that genes in these regions have more mutations than expected . . .” said Getz in a statement. “Now we know that this could have been just by chance so there is really no evidence that these genes are actually involved in cancer.”

To overcome the problem, Getz’s team developed an algorithm that factors in the presence of highly mutable genes. When applied to previous analyses of cancer genome data, the effects of the new approach were dramatic. For example, the list of genes that might be associated with lung cancer came down from 450 to 11. “We believe that this tool should be used in all studies—small or large—since the resulting gene list more accurately represents genes that have undergone positive selection in cancer,” Getz said.

(Hat tip to Nature)



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Avatar of: S.Pelech-Kinexus


Posts: 6

June 19, 2013

The varying rates of mutation of individual genes in cancer genomes is likely a consequence of not only higher rates of proliferation with cancer cells, but also defects in DNA repair genes that normally act to reverse gene mutations. In the analyses of human tumours, it is not uncommon to find that about 0.4 to 0.8% of most genes feature mutations. Oncogenes and especially tumour suppressor genes feature much high rates of mutations. Interestingly, several genes also display much lower rates of mutation than average, some of which have no or only a few reported mutations. Often, these are critical genes for cell proliferation, and we refer to these as tumour requiring proteins (TRP's). It would seem that mutations in these genes are not well tolerated in tumour cells, and it is likely that cancer cells that acquire mutations in TRP's do not survive well. As a result, the remaining cancer cells in a tumour do not feature these particular mutations. TRP's may represent ideal targets for cancer drug development, since tumour cells may be addicted to them and because they undergo much lower rates of mutation that oncoproteins. It is possible that the development of drug resistance may be less problematic with TRP targets than oncoprotein targets.

Avatar of: David Rasnick

David Rasnick

Posts: 1

June 20, 2013




S.Pelech-Kinexus raises a crucial point that has never been addressed properly. So far, there is no way to determine what actually constitutes true positive cancer-causing mutations. 

However, there is a larger question that eventually must be addressed: Is the assumption that gene mutations cause cancer correct?

A growing number of scientists are convinced the answer is NO.

Carcinogens initiate the massive chromosomal imbalance present in all cancer cells. Chromosomal imbalance autocatalytically leads to genomic instability of all types, producing the myriad of cancer phenotypes—independent of gene mutations. A mountain of evidence supports this conclusion. Fortunately, the long-standing resistance to this view is progressively weakening.


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