A new step in cancer research

The clarity gleaned from a new perspective exists as much in medical science as any other aspect of life. Professor Susan Clark, Head of the Genomics and Epigenetics Division at the Garvan Institute of Medical Research, outlines a fascinating area of research her laboratory is exploring by examining DNA in 3D.

Can you explain your current research focus?

Let me first explain the new and exciting field of cancer research called epigenetics. Cancer can be thought of as a disease of the DNA. In any cancer cell there are many mistakes in the DNA sequence code, called genetic mistakes – but in addition to the genetic mistakes there are also multiple mistakes in how the DNA sequence is read, and these are called epigenetic mistakes. ‘Epi’ is the Greek word for above, and epigenetics literally means information above the DNA sequence.

My laboratory studies the genetic and epigenetic mistakes in cancer, using next generation high-throughput sequencing technologies. This allows us to more fully understand the causes of cancer and develop new biomarkers to detect cancer early and predict what the best treatment option for each individual is.

How does a 3D view change what we know about how we research, understand and treat cancer?

There are 3 billion letters in the DNA code, and if DNA were joined head to head, it would span two metres in length. So can you imagine the three dimensional engineering feat required by the cell to organise our DNA to allow only specific sets of genes to be expressed inside the nucleus?

“We hope to understand more about the mechanisms that lead to cancer growth and in particular resistance to drug treatments.”

Each cell-type expresses different gene sets, and therefore each cell needs a slightly different 3D structure, and therefore a slightly different epigenetic profile. It is a new and exciting field of research to map the 3D genome structure in the cell nucleus. By comparing the changes in 3D genome architecture and corresponding changes in the epigenetic information in a cancer cell, we hope to understand more about the mechanisms that lead to cancer growth and in particular resistance to drug treatments.

How did your research evolve into this space?

On 14 April 2003, the International Human Genome Sequencing Consortium announced the successful completion of the Human Genome Project. That is, the order of the 3 billion letters in the human DNA code is now no longer a mystery.

However, the DNA sequence information alone is not enough to answer all the big questions. It became clear that the next big challenge would be to understand how the DNA code is read in each cell, and how the genome is organised in 3D space.

My laboratory has developed new sequencing tools to decipher the epigenetic chemical information on top of the DNA sequence – called DNA methylation. We found that the decoration pattern of DNA methylation across the cancer genome was altered and this led to a change in cancer gene expression.

We are now investigating if a change in the DNA methylation pattern also leads to alterations in the 3D structure of the cancer genome.

"Innovation needs to start with the basic building blocks, and we are still only at the very beginning of understanding the epigenetic code."

What has surprised you in your latest research?

I am surprised at how tightly regulated the 3D genome structure is inside the cell nucleus. It reminds me of origami, where you might start out with the same piece of paper, but with different instructions, you can fold the paper into different 3D shapes.

We are finding that the core folding instructions are conserved in each cell type to provide the basic foundations of DNA architecture, but it is the subtle last folds of DNA that change in cancer.

What sorts of results or insights can now be gleaned from this?

The results tell us that the relationship between genetic changes in cancer and epigenetic changes is tightly linked. Understanding the change in the 3D structure and epigenetic patterns provides new insights into how a cancer cell evolves and can start to form in the earliest of stages of malignancy.

It is so very important that we invest in basic medical research in Australia so that we can discover more about the fundamental mechanisms involved in cell biology and disease. Innovation needs to start with the basic building blocks and we are still only just at the very beginning of understanding the epigenetic code and how it is written and interpreted in the cell.

In the future we hope to provide the public with more precise information about cancer prevention and a more comprehensive range of clinically useful tools for both genetic and epigenetic testing in order to detect cancers at earlier and more treatable stages.

Learn more about the latest cancer research at the Garvan Institute of Medical Research.