Tumour genomes contain thousands of mutations, which can be identified by Next- Generation Sequencing technologies. By studying the observed pattern of these somatic mutations across genomic regions, we are able to explore the basic cell mechanisms that produce them. The interplay between these mechanisms, such as internal and external insults that damage DNA, chromosomal replication, transcription, and DNA repair mechanisms, leads to mutational processes that give rise to heterogeneous patterns of somatic mutations across the genome.

We have detected, for instance interactions between the machineries of transcription regulation and nucleotide excision repair (NER). Specifically, we recently demonstrated that the binding of transcription factors to their binding sites hinder the efficiency of NER, resulting in the generation of a greater number of mutations in the transcription factor binding site than in neighbouring regions (Nature 2016).

We have also showed that differential mismatch repair leads to reduced number of mutations in exons (Nature Genetics 2017). We propose that the enhanced activity of mismatch repair in exons may be driven by the higher exonic levels of histone marks (H3K36me3).

More recently, we have discovered that nucleosome covered DNA shows a 10 bp periodicity on the rate of somatic and germline mutations. This periodicity tracks DNA minor groove facing toward and away from the histones, and we propose that this has contributed to the AT/CG 10-bp periodicity in eukaryotic genomes (Cell 2018).

Many cancer therapies produce mutations in surviving tumor and healthy cells of the patient. By analyzing more than 3500 whole-genomes of treated metastatic patients we uncovered the mutational footprints (or mutational signatures) of commonly used cancer treatments. These signatures allowed us to measure the mutational toxicity of these treatments across patients and organs (Nature Genetics 2019)