Mutational signature analysis: methods and applications to the clinic

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PROJECT SUMMARY Mutational signature analysis is a recent analytical approach for interpreting somatic mutations in the genome. It utilizes the sequence context of point mutations as well as the size and type of copy number and structural aberrations to decompose the observed mutational patterns into distinct 'signatures', some of which have been associated with specific biological processes. In this project, we will develop more robust and sensitive com- putational methods for mutational signature analysis and apply them to several clinically important questions. Our initial work has attracted a great deal of attention from clinicians, and we will analyze data from several clinical cohorts in close collaboration. In Aim 1, we will build upon our previous work to devise a method that can identify homologous recombination deficiency in cancer patients profiled on gene panels. Although whole-genome sequencing offers several advantages, gene panel sequencing remains as a pivotal platform in clinical care. Our method will enable signature analysis for gene panels from which only a small number of mutations can be observed. We will incorporate additional sources of information and identify biomarkers for patient stratification. In Aim 2, we will investigate other types of genomic instability such as mismatch repair deficiency, replication stress, and APOBEC mutagenesis. For example, although patients with mismatch repair deficiency generally respond better to immunotherapy, there is a considerable variation across patients. We will use mutational signatures to identify a subset of patients that respond better. In Aim 3, we will extend our method to data from circulating tumor DNA and single cell RNA sequencing to enable signature-based predictive modelling. In Aim 4, we will develop a generalized analytical framework for whole-genome and whole-exome signature analysis that will overcome the shortcomings of current approaches. We will use this new framework to build a high-quality reference catalog for the community.