Mechanisms driving mutational signatures

Exposure to carcinogens can elicit specific patterns of DNA damage (mutational signatures). The recent surge in whole-genome sequencing of normal and cancerous tissues has led to the identification of an increasing number of these signatures.

To date, there have been at least 96 distinct single-base pair and dinucleotide mutational signatures identified but the aetiology of many of these remains unknown. Some of these mutations likely result from error-prone translesion DNA synthesis over chemically altered bases, known as DNA base adducts. However, a significant gap remains in our understanding of the exact nature of these adducts, how they arise and how they contribute to mutation formation. Without addressing this fundamental gap, we cannot fully explain the origins of many mutational signatures or develop strategies to prevent them. Identifying these base adducts could reveal whether they arise from endogenous processes or exogenous sources and aid identification of the mutagens responsible and inform public health measures.

This challenge would allow the identification of the mechanisms that lead from insult to mutation, and ultimately, realise the potential of mutational signatures to inform cancer prevention. 

This challenge will require technological innovation to resolve the chemical composition of normal versus damaged DNA in an unbiased manner, expanding the identification of altered DNA bases beyond what is currently possible (overcoming limitations of abundance, co-occurrence and stability of adducts).

The discovery of novel exogenous and endogenous mutagens may prompt the development of a reimagined AMES test linking the mutagen to the base adduct and the genesis of a point mutation.

Addressing this challenge may require the collaboration of organic, synthetic and analytical chemists, state-of-the-art nucleic acid and small molecule mass spectrometry, and single molecule sequencing method development, as well as biologists with expertise in mutagenesis and DNA repair through to epidemiologists. 

This challenge will result in the ability to analyse the base composition of the genome in an unbiased manner, ushering in a new age of discovery for DNA base modifications.

Identifying the chemistry that initiates mutational signatures, will advance understanding of the mechanisms of cancer initiation and may allow new public health measures in cancer prevention to reduce cancer risk. 

DNA is like an instruction manual for our cells, telling them how to grow and function. But over time, DNA can be damaged by harmful substances in the environment (like pollution, tobacco smoke, or UV rays from the sun) as well as by natural mistakes that happen inside our bodies. This damage, called mutations, can sometimes lead to cancer. Each mutation leaves behind a unique pattern of DNA damage, known as a mutational signature. These signatures act like forensic clues, helping scientists figure out what caused the DNA damage in the first place. Imagine an autograph on a piece of paper, if you don’t recognise the name, it’s just a scribble. But if you can identify the person who signed it, it tells you something important. In the same way, mutational signatures can reveal whether damage to our DNA is due to external sources, like pollution or diet, or internal processes, like aging or faulty cell repair mechanisms. So far, scientists have identified different mutational signatures, but for many of them, we still don’t know what caused the damage. Without this knowledge, we can’t fully understand what triggers cancer, or how to prevent it.

This Cancer Grand Challenge aims to find the causes of cancer-driving mutations. This could lead to new ways to prevent cancer, such as public health policies that reduce exposure to harmful substances. By identifying and limiting these risks, we could help prevent more people from developing cancer in the future.