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Mechanisms of Mutagenesis


We study the molecular basis of mutations in cancers and in normal cells.

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Mechanisms of Mutagenesis


We study the molecular basis of mutations in cancers and in normal cells.

 

Cancer:  a Disease of Genome Instability

Cancer remains a major public health challenge in Canada and around the world.  The Canadian Cancer Society estimates that 1 in 2 Canadians will get cancer at some point in their lifetime, and 1 in 4 will die from the disease.  Broadly similar figures are observed in other industrialized nations, while even higher incidences occur in developing countries.

Cancers can arise when some cells accumulate mutations that alter the information encoded in their genomic DNA, such that these cells gain a growth advantage over neighbouring cells.  Mutations are a form of genome instability, which in turn, is an enabling characteristic of cancer.  As such, to better understand the origin of cancers in its most fundamental sense, we must understand the origin of mutations that can give rise to the cancers.

 
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Mutations, We Need Lots of Mutations


Mutations, We Need Lots of Mutations


To study mutations, you need mutations.
— Dmitry A. Gordenin, PhD

Mutations can occur after DNA is damaged by reacting with a mutagen, which can be a chemical, an enzyme, or a physical agent.  Each mutagen tends to create a specific "mutation signature", which includes the DNA sequence motifs that are mutated preferentially, the resulting DNA base substitution pattern, etc.

To infer mutation signatures in a statistically rigorous way, many thousands of mutations (that are induced by a test mutagen under controlled experimental conditions) must be analyzed.  For this purpose, our group utilizes a highly sensitized model system in budding yeast, where long stretches of single-strand DNA can be generated by temperature shifting.  Many mutations are created when the DNA is exposed in single-strand form, and then identified by whole genome sequencing.

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Mutation Signatures in Cancers


Mutation Signatures in Cancers


What Mutation Signatures Tell Us

Mutations signatures from some of the more obvious sources have been identified in cancers.  These include signatures from tobacco smoke, ultraviolet light, various DNA repair deficiencies, and immune system enzymes called APOBEC's.  However, the mutation signatures created by many other known or suspected carcinogens remain to be discovered.

Our group uses various molecular genetic, genomic, and bioinformatic approaches to infer the mutation signature caused by a test agent in the yeast model system.  Then, we apply related approaches to query whether the same signature occurs in human cancers, and if so, to what extent.  Our research sheds important new light on the origin of mutations in cancer, which can empower the development of better cancer prevention, diagnosis, and treatment strategies.