Skip to 0 minutes and 14 seconds One exciting new field to emerge from cancer research in recent years is cancer genomics, the study of the cancer genome. This has happened because DNA sequencing technology has advanced to the point where it’s now fast enough and cheap enough to sequence whole genomes of individual cancer samples. These are then compared to the genomes of normal cells to identify the specific mutations and changes in each cancer. Cancer genomics helps us to understand basic cancer biology, but also to improve diagnosis and treatment. Many different cancer genomes are now being sequenced by many laboratories all around the world, as shown here in a map of projects of the International Cancer Genome Consortium. So first, what exactly is sequenced?
Skip to 1 minute and 6 seconds The genome is the complete DNA sequence of a cell. But this is very large, so often, only the exome is sequenced– that is, only the parts of the genome that can be transcribed into messenger RNA, and therefore encode proteins. Also, not every gene is expressed in every cell type. We can also sequence all of the RNAs that are made in a particular cell type. This is known as the transcriptome. Finally, as you’ve seen, epigenetic modifications can alter gene expression. And this can be disrupted in cancers. Scientists are now starting to catalogue all the epigenetic modifications in cancer cells, such as methylation. This is called the epigenome. So what have these large scale genome studies shown us?
Skip to 1 minute and 56 seconds First, many different genetic alterations can be seen in cancer cells. However, one important point is that changes in cancer cells can be classified into two types– driver and passenger. Driver mutations are changes that confer a selective growth advantage on the cell. In other words, they contribute directly to the cell becoming cancerous. They are therefore potential targets for cancer therapies. Passenger mutations, on the other hand, have no direct effect on cancer growth. These are random mutations that accumulate as a person ages, and also occur due to genomic instability in cancer cells. But they don’t contribute to the cancer.
Skip to 2 minutes and 41 seconds Secondly, the results show that certain genes are altered in multiple types of cancer, such as the tumour suppressor p53 and the oncogene KRAS, which you’ve already come across. But other genes are altered only in particular types of cancer. For instance, mutations isocitrate dehydrogenase, IDH, are particularly important in the brain cancer glioblastoma, but much less common in other cancers. The genome alterations identified as cancer drivers in these studies are likely to be good targets for the design of novel cancer therapies. Large scale sequencing studies have also shown that many cancers have specific mutation signatures– patterns of gene mutations and gene expression that are characteristic of that particular type of cancer.
Skip to 3 minutes and 32 seconds For instance, the leukaemia AML tends to have alterations in FLT3, NPM1, and DNMT3A. Pancreatic cancers tend to have a wide variety of mutations, but the most common changes are in RAS, p53, SMAD4, and CDK inhibitor 2. This is important, because it allows us to use therapies that target these specific genome changes– in other words, to tailor treatment to the individual cancer type. This should make treatment more effective and reduce side effects. In addition to identifying mutation signatures for different types of cancer, genome-wide studies have also shown that individual types of cancer– for example, breast cancer– can in fact be broken down into multiple subtypes. For example, this table shows four different genomic subtypes of breast cancer.
Skip to 4 minutes and 28 seconds It turns out that these subtypes are associated with different prognoses. For example, the luminal A breast cancer subtype has a better prognosis than the basal like subtype. This type of work has really exciting implications for diagnosis, prognosis, and treatment. It means we can sequence a patient’s cancer and classify it into a particular subtype. We can then give a more accurate prognosis and we can treat the patient with therapies designed specifically for that subtype, which will have a much better chance of success than if the same treatment was used for everyone. Another example is in pancreatic cancer. Genome studies have found that approximately 2% of pancreatic cancers have a mutation pattern that includes amplification of the HER2 oncogene.
Skip to 5 minutes and 18 seconds Although this subgroup is small, HER2-targeting therapies may be useful in these patients, such as Trastuzumab, which you’ve already come across as a therapy for HER2 positive breast cancers.
Skip to 5 minutes and 33 seconds Finally, the genetic alterations that we see in a particular cancer type are not just an unpredictable range of different mutations. They tend to fall into particular pathways. For instance, in breast cancer, the PI3-kinase cell survival pathway, P53 damage response pathways, and cell cycle checkpoint pathways are often lost. This is important because we may be able to use treatments that target a particular pathway, even if there is no drug available that targets an individual mutated gene. Genome-wide studies are large and expensive and require a coordinated effort from multiple laboratories. Many patient samples, and robust sampling and analysis methods are needed. However, these studies hold a great deal of promise for improving care for cancer patients.
Skip to 6 minutes and 25 seconds In fact, clinical trials are currently being carried out using treatments tailored to the genomic subtype of patients’ individual cancers– for example, in the IMPaCT trial for pancreatic cancer. Cancer genomics has the potential to make personalised therapy a reality and it seems likely that this type of research will continue to provide advances in cancer diagnosis and treatment.
Genome-wide studies in cancer
Dr Sarah Meek summarizes the developments in larger-scale genomic research which may ultimately revolutionise how we think about and treat cancer.
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