Drs. Eric McGinnis (left) and Ryan Stubbins (right) are recipients of the 2022/2023 Precision Health Catalyst Grant award for their project entitled “Rapid targeted gene sequencing and high-resolution optical genome mapping to optimize selection of targeted therapies in acute myeloid leukemia”
Read a summary of the project here.
“This project aims to: 1) Evaluate the feasibility, in a clinical laboratory, of high resolution rapid genomic testing using nanopore LRS and OGM in AML and 2) Evaluate the increase in clinical yield of combined OGM and LRS relative to current standard-of-care methods for timely identification of therapeutically actionable or diagnostic entity-defining genetic abnormalities.”
1. Can you tell us about the precision health research work you’re collaborating on?
In acute myeloid leukemia (AML), the genetic abnormalities we are able to identify in a clinical laboratory in cancer cells play a central role in how we diagnose these cancers and how patients are treated – in many cases determining what type of chemotherapy a patient receives and whether they will undergo bone marrow transplant. In addition to this, identifying genetic drivers in AML often results in patients being eligible for targeted, precision therapies that have been demonstrated to significantly improve outcomes. In many clinical laboratories the bulk of this work is done using decades-old technologies (mainly banded karyotyping) which have limited ability to resolve small or subtle changes in combination with highly targeted sequencing covering a small portion of the genome, and many genetic changes in cancer cells which could potentially inform diagnosis and treatment are not detectable as a result. Up to 25% of patients can have additional genetic drivers identified by newer technologies, and this can also identify targetable lesions. Our research explores applications of two newer technologies, optical genome mapping (OGM) and nanopore-based whole-genome long read sequencing (LRS) using adaptive sampling-based enrichment to clinical testing for patients with AML to determine the potential added benefit of applying these higher resolution tests as well as their feasibility of use in a clinical laboratory setting.
2. What results have you seen so far?
We observed that applying OGM and LRS to detection of genetic abnormalities in AML identifies an enormous number of abnormalities not detected by established standard-of-care testing – in the case of OGM often hundreds to thousands of such changes and in the case of LRS (in preliminary results) several orders of magnitude higher as this technology detects sequence abnormalities. These technologies have inherent advantages (for example the ease of translation of OGM for detection of structural variants and the higher overall resolving power of LRS to incorporate sequence-level variants) and disadvantages, including technical hurdles to implementation still being evaluated to enable us to fully understand the potential strengths of these tests separately and in combination. As we identify more of these previously hidden genetic changes in AML, we are also increasingly realizing that more clinical research is needed to understand how we apply these changes in clinical practice. A key focus of our research is now to understand how the additional genetic variation now detectable can inform treatment of patients with AML and other diseases to inform a precision medicine approach to diagnosis and therapy selection.
3. From your perspective, what do you think is exciting about the future direction of precision health?
It is clear from results of this and other similar studies that we are only beginning to scratch the surface with our understanding of diseases like AML, and with the rapid evolution of genomics technologies such as OGM and LRS (among many others) and their translation to clinical applications the potential for refinement in our approaches to diagnosing and treating these diseases is enormous – diseases we now think of as relatively homogenous entities in the context of our limited understanding may be meaningfully picked apart based on their underlying biology, and patients may derive substantial benefit. The use of these technologies has already started to change how we think about patients with AML and is now starting to change how we treat. With the availability, wider application, and improving understanding of these tools, we are excited at the emerging prospect of truly personalized and precision cancer medicine, in which understanding of the biology of a patient’s malignancy, developed through genomics and related techniques, can be exploited to meaningfully improve outcomes.
About Drs. Eric McGinnis and Ryan Stubbins
Dr. Eric McGinnis is a Hematopathologist at Vancouver General Hospital with subspecialty expertise in cancer cytogenetics and molecular genetics and a Clinical Assistant Professor at the University of British Columbia. His main research interests are in improving evaluation and classification of chronic myeloid neoplasms and acute leukemias through clinical applications of novel genomics technologies, particularly optical genome mapping and long read sequencing.
Dr. Ryan Stubbins is a Hematologist and Transplant/Cell Therapy physician in the Leukemia/BMT program of BC. He previously did his medical school, residency training, a MSc, and hematology/BMT training at the Universities of Saskatchewan, Alberta, and British Columbia. He has performed additional research training at the BC Cancer Genome Sciences Center and the University of Chicago. He has clinical and research interests are focused on cell therapy, transplantation, and its application to hematologic malignancies.