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Skin and lung cancer genomes are truly groundbreaking

Posted Dec 16 2009 12:00am
Pleasance ED et al. (2009) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. doi:10.1038/nature08629

A 'circus plot' of mutations in the lung cancer genome

It’s been a bumper week for research on cancer. As we report elsewhere, scientists have been delving deep into our cells’ DNA repair mechanisms, and finding out how they tick.

At the opposite end of the spectrum, two more papers published in Nature today look at what happens when DNA repair goes wrong, by mapping DNA damage across the whole genome of two types of cancer – melanoma and lung cancer.

What’s so remarkable – and groundbreaking – about these papers is not that they find new genes involved in cancer. It’s that the technique the scientists used to identify genetic damage allows them to identify what caused these mutations – and also build up a picture of how the cancers developed, on a molecular level.

This is a veritable treasure-trove of scientific information – the sort that has the potential to unlock some of cancer’s deepest secrets.

We’ve covered the ins and outs of these two papers on our News feed – but briefly, researchers at The Wellcome Trust Sanger Institute in Cambridge sequenced the entire DNA genome from the cells of two cancer patients – one with lung cancer, one with melanoma, and also from healthy cells from the same individuals. This allowed them to compare the two and pinpoint mutations scattered around the cancers’ DNA.

The stark finding was that the melanoma cell contained more than 33,000 mutations; the lung cancer one about 23,000.

They also saw evidence of how the cells had desperately tried to repair their damaged DNA in the face of a carcinogenic onslaught.

A key implication of their findings is that there was no stand-out “master switch” for cancer – instead, it confirms the idea that cancer occurs after a number of key cellular processes become damaged over time.

In fact, the beauty of the data is that the researchers should now be able to reconstruct the events that led to cancer in the first place – a sort of molecular archaeology dig.

Context, not content

As we alluded to earlier, this wasn’t a typical ‘gene hunting’ exercise – it was much more than that. By analysing the ‘context’ of each mutation – i.e. the DNA sequences that appear either side of it – researchers were able to glean clues as to what caused each one.

As you’d imagine, the cancer genomes both bore the tell-tale signs of their causes – tobacco smoke in the case of lung cancer, and UV radiation in the case of skin cancer.

As lead researcher Professor Peter Campbell said of the lung cancer finding:

“The profile of mutations we observed is exactly that expected from tobacco, suggesting that the majority of the 23,000 we found are caused by the cocktail of chemicals found in cigarettes. On the basis of average estimates, we can say that one mutation is fixed in the genome for every 15 cigarettes smoked”

Why skin and lung cancers?

The researchers chose skin and lung cancers because they’re two forms of the disease that have well-defined causes. This allowed researchers to test the theory that they’d be able to see ‘fingerprints’ of tobacco smoke and UV radiation all over the cancer genomes.

But other types of cancer don’t have such clear cut causes. The great hope now is that scientists can use this technique to identify the chains of events that lead to other cancers. Indeed, partial progress has already been made in this arena – in September a group of researchers, including Cancer Research UK’s Professor Carlos Caldas, published data on the breast cancer genome, and another US group has sequenced the genome of a patient with acute leukaemia.

Next generation sequencing

These studies were only possible thanks to the extraordinary advances in ‘massively parallel’ gene-sequencing technology over the last few years. And as this technology continues to progress, we’ll see more studies like these, generating reams of new information for scientists to pore over.

The decade began with the publication of the first draft of the human genome in 2000. It’s now ending with a flurry of papers that build on the Human Genome Project, and yield new and exciting insights into how cancer develops – insights that are sure to turn, eventually, into benefits for people affected by the disease.

Henry


Reference:

Pleasance, E. et al (2009). A comprehensive catalogue of somatic mutations from a human cancer genome Nature DOI: 10.1038/nature08658

Pleasance, E. et al (2009). A small-cell lung cancer genome with complex signatures of tobacco exposure Nature DOI: 10.1038/nature08629

Shah, S. et al (2009). Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution Nature, 461 (7265), 809-813 DOI: 10.1038/nature08489

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