Lists of Cancer Mutations Awash With False Positives _ Nature News & Comment

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6/17/13 Lists of cancer mutations awash with false positives : Nature News & Comment

www.nature.com.libproxy.uml.edu/news/lists-of-cancer-mutations-awash-with-false-positives-1.13206

Heidi Ledford

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NATURE | NEWS

Lists of cancer mutations awash with false positivesBut researchers show artefacts can be reduced by taking differing rates of mutation into

account.

17 June 2013

Some call them the fishy genes: errors in DNA that seem

to be associated with tumours, but which researchers

trawling through cancer genome data cannot explain. For

instance, why would mutations in genes involved in the

sense of smell be linked to lung cancer?

A reanalysis of cancer genome data, published on

Nature's website 1, finally does away with the fishy genes

and a host of others thought linked to cancer by

accounting for how mutation rates vary between different

locations in the genome. The effects are drastic: in one

analysis, using the researchers' improved models whittled

down the list of genes potentially associated with lung

cancer from 450 to 11. The study could help cancer

researchers to focus their efforts on the genes that matter,

thus preventing them from wasting time by investigating

blind alleys.

This will affect future cancer genome projects, says Gad Getz, a computational biologist at the Broad

Institute in Cambridge, Massachusetts, who is a lead author on the study. The major sequencing projects fo

cancer genomes have incorporated the new models into their pipeline, he says, noting that previous

analyses many of which have been reported in high-profile publications are now being redone.

Suspicious patterns

All cells accumulate mutations, but cancer genomes tend to be particularly

riddled with errors in part because cancer involves the deactivation of

the cell's own repair mechanisms, and because tumour cells reproduce at

a faster rate than those in healthy tissue. Most mutations do not affect the

cell's life cycle, however, and thus are probably not involved in cancer.

Tumour cells, such as these from a lung cancer,

are riddled with genetic mutations, but many of

those are caused by the cancer rather than being

involved in causing the disease.

STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY
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Big science: The cancer

genome challenge

More related stories

To determine which mutations are important drivers of the disease,

researchers compare the genomes of many tumours and look for

mutations that occur more frequently in cancerous tissue than one would

expect due to random chance.

Many researchers had expected that as analyses began to include more tumour genomes, this search

would become more refined and the lists of candidate cancer genes would get shorter. Instead, the listsgrew longer. To find out why, Getz and his colleagues looked for other factors that might boost mutation

rates.

In some cases, that higher rate of mutation was not linked to cancer, but to confounding factors, the team

demonstrated. To identify the false positives, they took into account the fact that genes that are less often

transcribed into RNA are more susceptible to mutating. This is because the transcription process is coupled

with a DNA repair process that can undo some mutations. Genes that produce very low levels of RNA as

would be the case for an olfactory gene in lung cells, say are therefore more likely to show as false

positives.

The team also took into account the different rates at which mutations can occur during DNA replication.

Genes that are copied later in the process are more likely be copied incorrectly because the enzymes that

construct new DNA become error-prone when supplies of DNA's chemical building blocks run low.

Once these and other confounding factors were incorporated into their analyses, Getz's team found far

fewer mutations that seemed to be linked to cancer. Getz thinks that the new models could be used to

improve trawls through genome data from patients with other diseases as well.

The analysis upgrade is vital, says Tom Hudson, president of the Ontario Institute for Cancer Research in

Toronto, Canada. It is especially useful for researchers who must pick through the lists of putative cancer-

associated genes in search of the next drug target. It takes so much work to follow up on these hits, says

Hudson. Being able to weed out false positives is obviously very important certainly for the life of many

postdocs.

Nature doi:10.1038/nature.2013.13206

References

1. Lawrence, M. S. et al. Naturehttp://dx.doi.org.libproxy.uml.edu/10.1038/nature12213 (2013).

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Lists of Cancer Mutations Awash With False Positives _ Nature News & Comment