After receiving his MD from Queen’s University in Kingston, Ontario and a rotating internship at Lion’s Gate Hospital, North Vancouver, BC, Dr. Karsan practiced medicine in rural BC and the Northwest Territories before working as a volunteer with Médecins Sans Frontières. He then completed his residency in Hematological Pathology at the University of British Columbia (UBC) followed by a Research Fellowship at the University of Washington.

Currently, Dr. Karsan is Professor of Pathology and Laboratory Medicine at UBC, and Distinguished Scientist at Canada's Michael Smith Genome Sciences Centre at BC Cancer. Dr. Karsan has been supported by several prestigious awards over the years, including 10 years as a Clinician-Scientist awardee of the Canadian Institutes of Health Research, 10 years as a Scholar of the Michael Smith Foundation of Health Research and currently as the recipient of the John Auston BC Cancer Foundation Clinical Scientist Award.

Dr. Karsan is internationally recognized in the field of blood cancer research. His translational research lab has generated seminal work on the role of noncoding RNAs and innate immune signaling in blood cancers. He currently leads a team of six principal investigators in a Terry Fox Research Institute Program Project in acute leukemia research. He is a member of various international hematology committees including: the International Working Group for Prognosis in Myelodysplastic Syndromes (MDS), the Experimental Hematology Subcommittee of the Society for Hematopathology, and the Laboratory Assays Working Group for the Myeloid Malignancies Precision Medicine Initiative. In 2002, he co-founded the Centre for Blood Research at UBC with nine other principal investigators.

Dr. Karsan is also a recognized leader in delivering clinical genomic assays. He established the first clinically-accredited Next Generation Sequencing lab in Canada, the Centre for Clinical Genomics (CCG), which was among the first few in the world. The CCG delivers cancer genomic testing to the entire population of BC. This pioneering work in using next generation sequencing (NGS) technologies for clinical delivery has led to the development of various novel technologies for clinical genomic testing including a unique genetic barcoding system to track patient samples, development and implementation of clinical reporting software for NGS, development of a transcriptomic (RNA sequencing) test for leukemia and clinical validation of a non-invasive prenatal test (NIPT) by whole genome sequencing in partnership with the Prenatal Screening Program of BC. He has led clinical trials in leukemia and solid tumour genomics and hereditary cancer diagnostics. These innovations led to a reduction of wait times for hereditary cancer testing, reduced per test costs and have increased the breadth of genes being tested. His work has been recognized with the Health Employers Association of BC (HEABC) Gold Apple award for Innovation.

Affiliations
  • Professor, Department of Pathology and Laboratory Medicine, University of British Columbia
  • Member, Experimental Medicine, University of British Columbia 
  • Founding Member, Centre for Blood Research, University of British Columbia 
  • Member, Stem Cell Network
Credentials

After receiving his MD from Queen’s University in Kingston, Ontario and a rotating internship at Lion’s Gate Hospital, North Vancouver, BC, Dr. Karsan practiced medicine in rural BC and the Northwest Territories before working as a volunteer with Médecins Sans Frontières. He then completed his residency in Hematological Pathology at the University of British Columbia (UBC) followed by a Research Fellowship at the University of Washington.

Currently, Dr. Karsan is Professor of Pathology and Laboratory Medicine at UBC, and Distinguished Scientist at Canada's Michael Smith Genome Sciences Centre at BC Cancer. Dr. Karsan has been supported by several prestigious awards over the years, including 10 years as a Clinician-Scientist awardee of the Canadian Institutes of Health Research, 10 years as a Scholar of the Michael Smith Foundation of Health Research and currently as the recipient of the John Auston BC Cancer Foundation Clinical Scientist Award.

Projects

Automation of the Clinical Bioinformatics Pipeline at the Centre for Clinical Genomics (Genome BC)

The aim of this project is to streamline the clinical bioinformatics pipeline by creating an automated and modular framework that will reduce training time, reduce reporting turnaround time, facilitate adaptation to new tools and changes to wet lab processes and reduce errors through tracking of information from the entire pipeline.

Development of an automated end-to-end next generation sequencing assay to detect all classes of genetic variant in a single diagnostic test

The aim of this project is to create a single genetic assay that will provide a comprehensive panel of cancer mutations required for both standard therapy and for patients to participate in cancer research.

The Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation

The long term goal of this project is to better understand the difference between normal blood forming cells and leukemic cells. The lab aims to identify and exploit vulnerable disease causing pathways that may be shared across different types of acute leukemias.

Selected Publications

Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype.

Nature medicine, 2010
Starczynowski, Daniel T, Kuchenbauer, Florian, Argiropoulos, Bob, Sung, Sandy, Morin, Ryan, Muranyi, Andrew, Hirst, Martin, Hogge, Donna, Marra, Marco, Wells, Richard A, Buckstein, Rena, Lam, Wan, Humphries, R Keith, Karsan, Aly
5q- syndrome is a subtype of myelodysplastic syndrome characterized by severe anemia and variable neutropenia but normal or high platelet counts with dysplastic megakaryocytes. We examined expression of microRNAs (miRNAs) encoded on chromosome 5q as a possible cause of haploinsufficiency. We show that deletion of chromosome 5q correlates with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a, and we identify Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP) and tumor necrosis factor receptor-associated factor-6 (TRAF6) as respective targets of these miRNAs. TIRAP is known to lie upstream of TRAF6 in innate immune signaling. Knockdown of miR-145 and miR-146a together or enforced expression of TRAF6 in mouse HSPCs resulted in thrombocytosis, mild neutropenia and megakaryocytic dysplasia. A subset of mice transplanted with TRAF6-expressing marrow progressed either to marrow failure or acute myeloid leukemia. Thus, inappropriate activation of innate immune signals in HSPCs phenocopies several clinical features of 5q- syndrome.

Fixation Effects on Variant Calling in a Clinical Resequencing Panel.

The Journal of molecular diagnostics : JMD, 2019
Parker, Jeremy D K, Yap, Shyong Quin, Starks, Elizabeth, Slind, Jillian, Swanson, Lucas, Docking, T Roderick, Fuller, Megan, Zhou, Chen, Walker, Blair, Filipenko, Douglas, Xiong, Wei, Karimuddin, Ahmer A, Phang, P Terry, Raval, Manoj, Brown, Carl J, Karsan, Aly
Formalin fixation is the standard method for the preservation of tissue for diagnostic purposes, including pathologic review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic test results. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade, laboratory-developed targeted resequencing assay. Several parameters relating to sequencing quality and variant calling were examined and quantified in tumor and normal colon epithelial tissues. We identified an alternative fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathologic review.

Sample Tracking Using Unique Sequence Controls.

The Journal of molecular diagnostics : JMD, 2020
Moore, Richard A, Zeng, Thomas, Docking, T Roderick, Bosdet, Ian, Butterfield, Yaron S, Munro, Sarah, Li, Irene, Swanson, Lucas, Starks, Elizabeth R, Tse, Kane, Mungall, Andrew J, Holt, Robert A, Karsan, Aly
Sample tracking and identity are essential when processing multiple samples in parallel. Sequencing applications often involve high sample numbers, and the data are frequently used in a clinical setting. As such, a simple and accurate intrinsic sample tracking process through a sequencing pipeline is essential. Various solutions have been implemented to verify sample identity, including variant detection at the start and end of the pipeline using arrays or genotyping, bioinformatic comparisons, and optical barcoding of samples. None of these approaches are optimal. To establish a more effective approach using genetic barcoding, we developed a panel of unique DNA sequences cloned into a common vector. A unique DNA sequence is added to the sample when it is first received and can be detected by PCR and/or sequencing at any stage of the process. The control sequences are approximately 200 bases long with low identity to any sequence in the National Center for Biotechnology Information nonredundant database (<30 bases) and contain no long homopolymer (>7) stretches. When a spiked next-generation sequencing library is sequenced, sequence reads derived from this control sequence are generated along with the standard sequencing run and are used to confirm sample identity and determine cross-contamination levels. This approach is used in our targeted clinical diagnostic whole-genome and RNA-sequencing pipelines and is an inexpensive, flexible, and platform-agnostic solution.

Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling.

Cell reports, 2019
Coulombe, Patrick, Paliouras, Grigorios N, Clayton, Ashley, Hussainkhel, Angela, Fuller, Megan, Jovanovic, Vida, Dauphinee, Shauna, Umlandt, Patricia, Xiang, Ping, Kyle, Alistair H, Minchinton, Andrew I, Humphries, R Keith, Hoodless, Pamela A, Parker, Jeremy D K, Wright, Joanne L, Karsan, Aly
The sterile alpha motif (SAM) and SRC homology 3 (SH3) domain containing protein 1 (Sash1) acts as a scaffold in TLR4 signaling. We generated Sash1{{sup}}-/-{{/sup}} mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a delay in maturation of alveolar epithelial cells causing reduced surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and endothelial nitric oxide synthase (eNOS) in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells affects alveolar epithelial cells in a cGMP-dependent manner, inducing maturation of alveolar type 1 and 2 cells. Thus, we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 regulates alveolar epithelial cell maturation and promotes pulmonary surfactant production through nitric oxide signaling. Lung immaturity is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy.

Genomic testing in myeloid malignancy.

International journal of laboratory hematology, 2019
Docking, T Roderick, Karsan, Aly
Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single-gene testing to an era dominated by next-generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome-based testing may offer several distinct benefits beyond traditional DNA-based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single-gene tests to the era of NGS panels and genome-wide sequencing-highlighting both the potential and drawbacks of these novel technologies.

miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling.

Nature communications, 2018
Lam, Jeffrey, van den Bosch, Marion, Wegrzyn, Joanna, Parker, Jeremy, Ibrahim, Rawa, Slowski, Kate, Chang, Linda, Martinez-Høyer, Sergio, Condorelli, Gianluigi, Boldin, Mark, Deng, Yu, Umlandt, Patricia, Fuller, Megan, Karsan, Aly
Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor β (TGFβ) pathway as key targets of miR-143/145. Enforced expression of the TGFβ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145{{sup}}-/-{{/sup}} mice. Despite reduced HSC activity, older miR-143/145{{sup}}-/-{{/sup}} and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFβ/DAB2 activation, and loss of these miRNAs creates a preleukemic state.

Applications of Bayesian network models in predicting types of hematological malignancies.

Scientific reports, 2018
Agrahari, Rupesh, Foroushani, Amir, Docking, T Roderick, Chang, Linda, Duns, Gerben, Hudoba, Monika, Karsan, Aly, Zare, Habil
Network analysis is the preferred approach for the detection of subtle but coordinated changes in expression of an interacting and related set of genes. We introduce a novel method based on the analyses of coexpression networks and Bayesian networks, and we use this new method to classify two types of hematological malignancies; namely, acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Our classifier has an accuracy of 93%, a precision of 98%, and a recall of 90% on the training dataset (n = 366); which outperforms the results reported by other scholars on the same dataset. Although our training dataset consists of microarray data, our model has a remarkable performance on the RNA-Seq test dataset (n = 74, accuracy = 89%, precision = 88%, recall = 98%), which confirms that eigengenes are robust with respect to expression profiling technology. These signatures are useful in classification and correctly predicting the diagnosis. They might also provide valuable information about the underlying biology of diseases. Our network analysis approach is generalizable and can be useful for classifying other diseases based on gene expression profiles. Our previously published Pigengene package is publicly available through Bioconductor, which can be used to conveniently fit a Bayesian network to gene expression data.
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