Glossary

What is INSIGNIA?

INSIGNIA is a study focused on the investigation of patterns of mutations (signatures) in inherited and other progressive genetic diseases.

Cancer is the ultimate genetic disease characterised by many thousands of mutations that accumulate within the genome of a cancer patient. The sets of mutations observed in a cancer genome are the overall outcome of a number of different mutational processes. These are caused by an underlying mechanism of DNA damage, and subsequent attempts by the cell to repair that damage. As a result, each mutational process will leave a distinctive mark or mutational signature on the cancer genome.

In the same way that counting tree rings can tell us about the age and growth of that tree, the mutational signatures 'buried in the genome' can provide us with information on the biological changes that have occurred during the course of cancer (or other genetic disease) development.

Computational (bioinformatic) approaches, in conjunction with the latest sequencing technologies have been used to explore mutagenesis in cancers. Analysis of the sequences of whole-genomes from patients with cancer has proved that mutational signatures do exist (Nik-Zainal et al., 2012).

For example, the signature associated with ultraviolet (UV) damage has been uncovered in skin cancer, and tobacco-associated signatures have been found in lung cancers (Alexandrov et al., 2013). In addition, a number of novel signatures have been identified, but the causes of many of these remain unknown.

What we do know is that DNA is subjected to a constant barrage of damage from both within the cells and from the external environment (e.g. UV light from the sun). To deal with this, our cells are equipped with a number of different DNA repair pathways that attempt to remove the damage and restore the DNA back to normal. We think that in cancer cells, many of the components of DNA repair pathways go wrong or are faulty, resulting in some of these patterns of mutagenesis.

To understand this process better, we are looking to recruit patients with known or suspected defects in DNA repair, or who have been exposed to chemicals that damage DNA, so that we can study the patterns of mutations in their genomes. This will allow us to see whether specific 'errors' can be linked to particular signatures.

This information will then be used to create a database of signatures, designed to function in the future as an information resource for users regarding the biological changes have occurred in their cancers or other progressive genetic disorders.

 

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