A couple of weeks ago, the charity I work for hosted the 2nd International Triple-Negative Breast Cancer Conference at Church House, London. On a long list of distinguished speakers was newly knighted, Professor Sir Mike Stratton, from the Sanger Institute in Cambridge. Mike Stratton has strong links with the charity I work for (Breakthrough Breast Cancer), having been involved in some of their earliest funded research, which resulted in the discovery of the BRCA2 gene.
Professor Stratton has been a key player in the emergence of whole cancer genome sequencing and its use for advancing cancer research. He started the Cancer Genome Project at the Sanger Institute; work which led to the identification of cancer-causing mutations to a gene called BRAF and rapidly led to the development of successful treatments. Most recently he embarked on an ambitious project to understand the mutational processes that continually bombard DNA and lead to the development of cancer. It was the impact of this work on breast cancer research that Mike presented at the conference.
Mike’s work grew out of a hypothesis that cancers could be defined by the genetic mutations they have accumulated through-out their life. It was known that different mutagens (such as tobacco or UV-radiation) cause very specific types of mutation to DNA but what we didn’t yet know was how large numbers of these mutations combine over time to produce what is called a ‘mutational landscape’. So the question Mike wanted to address was can we define cancers by their mutational signature (or landscape) and use this information to understand the mutational processes that mould cancer genomes?
Taking whole genome sequences of tumours from over 7000 cancer patients, ranging across 30 different types of cancer, the team found that all human cancers shared 21 mutational signatures. Some of these signatures were common to all cancers, suggesting they are early stage mutations that may drive cancer initiation. Others were restricted to single types revealing specific genomic patterns attributed to certain cancers. With regards to breast cancer, Mike and his team showed that 5 of the 21 signatures were operative, but the combination of these 5 signatures was highly diverse across individual breast cancer cases.
They used this information to mine the literature and find a protein that may be responsible for producing the kind of mutations they were seeing in breast tumours. What they discovered was a protein called APOBEC could explain the signatures observed in breast cancer patients. What was of particular interest was that APOBEC is usually involved in the immune response to viral infection such as HIV or Hepatitis B. The suggestion made was that response to a virus early on in life may cause an increase in the activity of APOBEC, which if remains sustained, could produce cancer causing mutations and the signatures observed in Stratton’s analysis.
Even more remarkable then this finding was the presence of a genetic phenomenon termed by the team as ‘kataegis’ – Greek for thunderstorm. Kataegis refers to clusters of mutations that appear in cancer genomes at defined regions along DNA. They are beautifully represented in ‘rainfall plots’ which show clusters of mutations and their position along the genome. When the team took a closer look at the mutational signatures of breast cancer they noticed that many of them were similar types and wondered if APOBEC could be responsible for kataegis. It turns out that yes it can. When you genetically engineer yeast to make lots of APOBEC their genomes show a similar pattern of kataegis.
So there appears to be a role for APOBEC driving historical mutations that could, in turn, drive more mutations in the region and result in kataegis. This is highly significant because it gives a sort-of ‘back in time’ perspective of cancers genetics. This in-depth information could have massive impact on our understanding of cancer causation and what we can do to prevent and treat it in the future. I think that this work really highlights the power of whole genome sequencing and if anything, demonstrates why we need to continue funding genomics research. Mike Stratton has done exceptional work to lead the way in cancer genomics and his contributions to science are in doubt deserving of a knighthood.