Cancer arises when a single cell acquires genetic alterations leading to uncontrolled replication. As tumour cells divide they continue to acquire genetic mutations which they pass on to their descendants, forming distinct subpopulations with different characteristics. The ability of tumours to generate genetic diversity and evolve in response to selective pressures can enable them to develop resistance to treatment. Certain forms of genetic alteration have been associated with poor patient survival in high grade serous ovarian cancer. Understanding the frequency with which these alterations arise within tumours and the diversity they generate requires profiling the genetic material of individual cancer cells. We will optimize experimental approaches for sequencing single tumour cells and develop computational and statistical methods to characterize this genetic diversity. This will provide researchers with new tools with which to study the mechanisms that underlie treatment resistance and patient relapse, and open the door for the development of new prognostic measures and therapeutic approaches.
Research Location: Canada's Michael Smith Genome Sciences Centre
Comprehensive dissection of tumor evolution in pediatric acute myeloid leukemia using single cell methylation sequencing
Pediatric acute myeloid leukemia (pAML) is a common type of cancer in children and is diagnosed in roughly 40 Canadian children each year. Although 90% of all children respond well to the initial treatment the cancer comes back for 20% of the children while being resistant to treatment, leading to a poor outcome. Current studies of treatment resistant cancers are not able to detect rare but important cells that form the cancer, which may be especially important in how treatment resistance occurs. Fortunately, new technologies allow for measurements from each of the thousands of individual cancer cells that form the tumor allowing us to detect rare cancer cells, including those that may result in treatment resistant disease. For the first time, we aim to use these technologies to focus on chemical properties of the DNA that influence how the DNA is interpreted, or read, by the cell. By studying patterns of these chemical properties in rare cancer cells and also normal cells we aim to learn if, and how, these patterns contribute to the phenomenon of treatment resistance in pediatric AML. With this knowledge, our ultimate goal is to prevent the formation of treatment resistant disease in this vulnerable population of patients.
Defining the landscape of genetic variation underlying rare human disease using nanopore long-read sequencing
Collectively, rare diseases affect millions of people worldwide. Understanding the molecular cause of rare disease has important implications for clinical management. However, although most rare diseases are suspected to be genetic in origin, the causal genes are not known in a majority of affected families. This study will use emerging technologies to better understand the molecular basis of rare genetic diseases. Long-read genome sequencing, a recent genetic testing technology, will help us to identify rare and complex genetic changes in individuals suspected to have harmful genetic variation. These findings will allow us to study how specific genes lead to congenital disorders and adult-onset cancer predisposition syndromes, genetic syndromes that increase the risk of developing specific types of cancers. This research will improve our understanding of normal and disease-causing genetic variation and help establish a foundation for the broader application of new technologies in the clinic.