Abstract
Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or “mutation signatures” at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis.
Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites.
We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5’ to the mutated site.
The overall framework of our work is based on probabilistic models that are closely connected with “mixed-membership models” which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods.
Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.
Author Summary Somatic (non-inherited) mutations are acquired throughout our lives in cells throughout our body. These mutations can be caused, for example, by DNA replication errors or exposure to environmental mutagens such as tobacco smoke. Some of these mutations can lead to cancer.
Different cancers, and even different instances of the same cancer, can show different distinctive patterns of somatic mutations. These distinctive patterns have become known as “mutation signatures”. For example, C > A mutations are frequent in lung caners whereas C > T and CC > TT mutations are frequent in skin cancers. Each mutation signature may be associated with a specific kind of carcinogen, such as tobacco smoke or ultraviolet light. Identifying mutation signatures therefore has the potential to identify new carcinogens, and yield new insights into the mechanisms and causes of cancer,
In this paper, we introduce new statistical tools for tackling this important problem. These tools provide more robust and interpretable mutation signatures compared to previous approaches, as we demonstrate by applying them to large-scale cancer genomic data.
Footnotes
↵* yshira{at}hgc.jp; mstephens{at}uchicago.edu
