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Largest-ever cancer gene survey shows how common alterations affect cancer risk

Breast cancer cells. © Inserm/ Gilles Evrard
Breast cancer cells. © Inserm/ Gilles Evrard

The largest cancer genetic survey ever conducted is revealing how common gene alterations influence our cancer risk – and the results could potentially enable better prevention and screening.

The EU-funded COGS project has examined the genetics of 250 000 individuals collected during existing studies on breast, ovarian or prostate cancer worldwide. Launched in May 2009, with EUR 12 million of funding, it involves around 1 000 scientists from over 160 research groups globally.

Although many previous studies have looked at the effects of genes and environment on cancer, COGS is the largest to date, said Professor Per Hall, an epidemiologist at the Karolinska Institute in Stockholm, Sweden, who coordinates the project with Professor Douglas Easton at the University of Cambridge, UK.

The sheer size of the project gives it a statistical power beyond previous work, he said. This means that it may be able to offer insights which smaller studies cannot. It is also the first study to look at three cancers at the same time.

‘If you have these large numbers, you are able to identify even very small influences,’ Prof. Hall said.

The study has so far identified genetic alterations associated with breast cancer. These alterations, also known as alleles, are tiny changes in DNA sequences called single nucleotide polymorphisms, or SNPs.

SNPs are the tiny variations between the DNA sequences of individuals. One of the four letters, known as nucleotides, of our DNA alphabet may differ from person to person at a given location. And these differences may be perceptible only through genetic sequencing, as SNPs most often occur in regions of the genome that are non-coding.

However, in recent years, some SNPs have been associated with disease risk and an individual’s susceptibility to environmental factors.

Carried by half the population

‘These markers (alterations) are very common,’ Prof. Hall said. Some are carried by one third or one half of the population, so they confer a very low risk, he said.

‘If you have these large numbers, you are able to identify even very small influences.’

Professor Per Hall, the coordinator of COGS

So far, COGS has found about 80 genetic alterations associated with breast cancer, Prof. Hall said. ‘If we only got one of these – for one out of 80, the influence is very small,’ he explained. But if the 80 SNPs are put together, a very different picture of cancer risk emerges: ‘We are able to identify high and low risk women.’

This is quite different from known breast cancer genes like BRCA1 and BRCA2. Prof. Hall said that while these are rare mutations which cause cancer risk to skyrocket, COGS is studying ‘very, very common mutations’.

Though identifying BRCA genes is extremely important for individuals, because they only account for up to 3 % of breast cancers, from a population perspective identifying BRCA mutations still leaves 97 % of cases which are explained by factors like lifestyle and other genetic susceptibilities. That means it is difficult to pin down the exact genes that can increase the risk of breast cancer.

‘The genome is far more complex than we could ever dream of. We don’t have a few genes which determine breast cancer or height, but thousands and thousands of them,’ Prof. Hall said.

Surprising results

The study’s first batch of papers were published in Nature Genetics and Nature early in 2013. And they produced some surprising results.

‘The amazing thing that we would never ever have thought would emerge is that we have found several genes actually influencing all three (cancers),’ Prof. Hall said. Breast, ovarian and prostate cancers were chosen for the study because they are all hormonally driven cancers. But there were unexpected associations.

Professor Per Hall, the coordinator of COGS. © Gustav MårtenssonProfessor Per Hall, the coordinator of COGS. © Gustav Mårtensson

Notably, alterations in a gene called TERT which influences the length of telomeres – the protective caps at the end of chromosomes, known to be linked to ageing – affected risk in all three cancers.

Though the researchers expected the three cancers to share some genetic components, Prof. Hall said: ‘We didn’t for our lives think it was to do with the TERT gene.’

They could see this because they used the same bespoke sequencing chip for all three cancers. Dubbed the iCOGS chip by the team, the array allowed researchers to examine about 200 000 SNPs, which they had spent nearly a year selecting, for every individual in the study.

The development of the chip also dramatically brought down the sequencing costs from about EUR 1 460 per DNA sample a couple of years before, to about EUR 29 per sample. The three cancers were studied together partly for scientific reasons, but also for financial ones.

The current funding for COGS expired in January 2014, but further research is needed, and the next thing will be to move on from identifying risk genes to building good prediction models, said Prof. Hall.

This might then help study how cancer screening might be changed, and also to study what kind of preventative measures might help people at high risk of these cancers.

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