Imagine being able to look at a tumor and decipher all the exposures the patient had experienced that led up to that cancer. This is the grand plan of scientists, such as Prof. Sir Michael Stratton, M.D., Ph.D., who are making inroads to defining the mutational signatures of different cancers. On Jan. 12, NIEHS welcomed Stratton, director of the Wellcome Trust Sanger Institute, to discuss "Mutation Signatures in Human Cancer."
"Mike is very well known across the world of scientists as an insightful leader in genomics and human genetics," said host Dmitry Gordenin, Ph.D., who leads the NIEHS Mechanisms of Genome Dynamics Group. Stratton established the Cancer Genome Project in 2000 and continues to break new ground in genomics.
Gordenin said Stratton’s visit stemmed from the mutual interest of NIEHS and Wellcome Trust Sanger Institute in identifying mutational processes that lead to complex phenomena, and studying those phenomena with both bioinformatics and mechanistic research. In 2016, NIEHS invited Gad Getz, Ph.D., from the Broad Institute, to discuss some of the specific mechanisms behind mutation signatures.
Signatures point to past exposures
"Most of us subscribe to the dogma that cancers are caused by somatic mutations, but we have a relatively indistinct view as to what processes cause these somatic mutations," Stratton explained. "And that’s quite remarkable because the things that cause these somatic mutations are the things that cause cancer." Somatic mutations occur in cells other than sperm and eggs, and are not passed on to children.
To study the underlying processes, Stratton looks at changes in DNA called base substitutions. Certain base substitutions are linked with specific exposures. For example, ultraviolet light causes one type of mutation, whereas tobacco exposure results in numerous mutations of a different type. These characteristic patterns are called mutation signatures.
"The concept that specific mutation patterns, or spectra, in somatic cells could reveal exposure history is an idea that was pioneered by many NIEHS scientists and grantees in the early 1990s," said Doug Bell, Ph.D., lead researcher of the NIEHS Environmental Genomics Group. "It is gratifying that the technical limitations have been overcome, and the idea has been extended in such a comprehensive way."
Lifetime of history in a single cell
Stratton compared the lineage of a single cell — from fertilized egg, through a lifetime of cell divisions, to late stage cancer — to a jazz composition filled with improvisation, or mutation. Using a mathematical process called non-negative matrix factorization, his team can extract each cancer’s mutational signatures, just as one might tease out the sounds of individual instruments in a band.
By studying cancer genomes, Stratton’s team works to identify mutational signatures and discover what processes lead to cancer. Analyzing 28,000 different cancers has produced fewer than 50 mutational signatures, he said. Some of those are found across all cancers, and others appear to be unique to a particular cancer.
Decoding mutation rate
Currently, Stratton is interested in identifying lifetime mutations in individual cells. This work has revealed that some mutational processes occur across all cells at a predictable rate. Cancer mutation rates may exceed those of normal cells. With a goal similar to that of Getz’s lab, Stratton’s team is working to associate mutational signatures with the exposures that lead to them.
Judging by the responses, the seminar inspired those in the packed auditorium, including Nobel Laureate Paul Modrich, Ph.D., from Duke University. Jack Taylor, M.D., Ph.D., senior researcher in the NIEHS Molecular and Genetic Epidemiology Group, was among the listeners intrigued by the potential of this research.
"Although the talk was focused on the evolution of tumors, the ability to measure mutations in single normal cells really opens the box to a lot of interesting questions," Taylor said. "Do people differ? Can we see the effect of age, exposure, and lifestyle reflected in the mutational pattern across different tissues? Can we construct a measure of mutational load, to assess meaningful past exposure and future risk of disease?"
(Simone Otto, Ph.D., is an Intramural Research and Training Award postdoctoral fellow in the NIEHS Ion Channel Physiology Group.)