Mutations are the fuel of evolution. They provide the variability that evolution can act on. This is true for organisms, but it is also the case in cancer. Normal cells accumulating mutations can increase their potential to replicate and survive. By a process of adaptation and selection, they eventually turn into a malignant tumour.
Cancer genomics projects have revealed huge heterogeneity in the types and numbers of mutations between patients with different cancer types. In some cases, these differences are clearly attributable to a particular carcinogen, such as tobacco smoke or UV light. In many cases, however, it is unclear why different tumours exhibit different mutations at different frequencies.
My research team studies the processes that cause mutations. By leveraging the wealth of publicly available data sets, we are trying to understand how environmental influences interact with cell biology and the genome to produce the patterns of mutations observed in human tumours. Over the years we have made several important discoveries:
Mutation density varies with chromatin structure
Epigenetic histone modifications affect how DNA is packaged in the nucleus. We demonstrated in 2011 that the distribution of certain histone marks predicts the density of somatic mutations in cancer genomes:
This important finding led to the improvement of cancer-driver-gene prediction programs that nowadays take into account this regional variability to avoid over-estimating the importance of some genes in cancer. More recently, other groups have used the defect we described to identify the cell-of-origin of cervical cancers, by comparing the histone modification maps of healthy cell types to the mutation patterns observed in cancer.
Methylation, but not hydroxy-methylation, correlates strongly with C -> T mutation rate
DNA modifications at cytosine (C) residues are another important epigenetic mechanism by which somatic cells can control the genome. However, it was observed long ago that the most frequently methylated C positions are also more frequently mutate to T. My group showed in 2016 that different types of cytosine modifications have different effects on mutagenesis. In particular, methylation, but not hydroxy-methylation, starkly increases the C to T mutation rate:
Based on these findings, we are now exploring the mechanisms that lead to mutations at methylated and hydroxy-methylated Cs.
Most mutagenic processes are influenced by DNA replication and the associated repair
Most mutagens cause damage to DNA or to individual DNA bases. To get a mutation, this damage needs to be fixed, usually through replication, into a normal but incorrect base pair. The processes in which DNA repair removes DNA damage are highly complex. In 2018, we showed that most mutational processes, represented by “mutational signatures”, are unevenly distributed on the two DNA strands depending on whether they were replicated as the leading or the lagging strand:
This finding emphasises how important it is to think of mutagenesis in the context of a living cell, where replication and the associated DNA repair pathways filter out mutations in a replication strand and timing-dependent manner.