Dr. Ryan D. Morin, PhD

Affiliations

Associate Professor, Simon Fraser University 
Associate Member, School of Computing Science, Simon Fraser University 

Professional Profile

Dr. Ryan Morin has been studying the genetic nature of lymphoid cancers using genomic methods for more than a decade. During his doctoral training at the University of British Columbia and BC Cancer, he pioneered the use of transcriptome and whole genome sequencing to identify driver mutations in non-Hodgkin lymphomas. Over the course of his training, he published a series of papers describing some of the most common genetic features of diffuse large B-cell (DLBCL) and follicular lymphomas including EZH2, KMT2D, CREBBP and MEF2B. Following his transition to an independent position at SFU, Dr. Morin has continued to identify genetic features of these and other aggressive lymphomas including non-coding (silent) regulatory drivers of cancer. His laboratory has implemented novel assays for the sensitive detection and genetic characterization of circulating tumour DNA (ctDNA). These “liquid biopsy” approaches continue to be developed as non-invasive methods for monitoring treatment response and resistance. Using these and other modern genomics tools and bioinformatics techniques, his team continues to explore the genetics of relapsed and refractory DLBCL with an ultimate goal of identifying novel biomarkers that predict treatment failure on specific therapies. This work has helped refine our understanding of genetic and gene expression differences that predict poor outcome in DLBCL.

Research Projects

Genetic and molecular mechanisms of treatment resistance in DLBCL

Non-Hodgkin lymphomas (NHL) represent the sixth most commonly diagnosed type of cancer in Canada with diffuse large B-cell lymphoma (DLBCL) being the most prevalent. DLBCL patients exhibit variable responses to available therapies such as R-CHOP. Some biomarkers beginning to enter clinical trials rely on gene expression signatures to identify high-risk cases. For example, DLBCL comprises two cell-of-origin (COO) subgroups with activated B-cell (ABC) cases typically having worse prognosis than germinal centre B-cell (GCB) cases. Therapeutics that exploit molecular features unique to each subgroup are being actively pursued but up-front identification of patients unlikely to achieve a durable response remains a challenge. Although existing methods can identify specific prognostic gene expression features, these capture only some of the clinical heterogeneity and require tumour RNA, which is not always available. Using comprehensive genomic analyses and by integrating mutation and expression data from over 2000 DLBCL tumours, we seek novel molecular features that are associated with treatment resistance in DLBCL. The ultimate goal of this work is to develop new predictive and prognostic biomarkers and identify new therapeutic targets for treatment-resistant DLBCLs.

Resolving clonal structure and evolution patterns in DLBCL

Diffuse Large B-Cell Lymphoma is a genetically heterogeneous form of cancer, with different cells in the tumour acquiring different mutations. This intra-tumour heterogeneity can have profound effects on treatment; if a clonal subpopulations is resistant to treatment, it will reform the tumour following treatment, causing the patient to relapse. We are recieving samples from several clinical trials exploring different salvage therapies for patients with relapsed DLBCL. Tumour biopsies and liquid biopsies are being collected from patients both before and after they are treated. Using these temporal sources of tumour DNA, we can identify clonal subpopulations in the tumour, and further explore how the tumour evolves and adapts in the face of a strong selective pressure such as treatment. The mutations unique to these resistant clonal subpopulations can be explored to determine which mutation(s) result in treatment resistance. We can further determine if these mutations are detectable prior to treatment, which may allow patient to be screened for resistance mutations before they are treated.

Comprehensive proteogenomic characterization of mantle cell lymphoma (MCL)

Mantle cell lymphoma is a rare cancer that derives from B lymphocytes in the periphery (mantle zone) of the germinal centre. MCL is most often diagnosed at stage 3 or 4 and is typically aggressive although some patients have an indolent form of the disease. Only 30-40% of patients with advanced disease achieving a complete response to frontline treatments (R-bendamustine). Heterogeneous clinical response is partially attributable to observable variations in morphology, immunophenotype and proliferative capacity; however, there is little known about the relationship between genetic features and variation in phenotype or response to specific treatment regimens. Through a meta-analysis of in-house and existing exome sequencing data, our group has identified multiple novel driver mutations in MCL including some that associate with high or low proliferation. To more completely ascertain the mutations that lead to lymphomagenesis in MCL, we are performing an integrative proteogenomic characterization of MCL tumours using a combination of whole genome sequencing, RNA-seq and shotgun proteomics. We are using these data to identify novel coding and non-coding (i.e. regulatory) driver mutations that affect the natural history of MCL including treatment response.

Identification and functional characterization of recurrent non-coding mutations in NHLs

The list of protein-coding drivers identified through sequencing in DLBCL has begun to saturate and yet there remains a gap in our understanding of how these genetic alterations contribute to the transcriptional differences underlying known prognostic signatures and molecular subgroups. For example, dysregulation of NF-κB is the hallmark feature of ABC DLBCL but many ABC cases appear to lack the common driver mutations that are known to promote NF-κB. We are seeking driver mutations that contribute to some features of NHLs. We use data-driven comprehnsive methods that allow identification of non-coding SSMs with a regulatory effect in cis or trans on genes/proteins relevant to malignancy.

Comprehensive characterization of endemic and sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is currently classified as one of three clinical variants: endemic BL, sporadic BL, and HIV-associated BL. The endemic variant is primarily diagnosed in sub-Saharan Africa and is epidemiologically associated with the Epstein–Barr virus (EBV) and malaria infection; although, the role of these pathogens in promoting the formation of BL remains unclear. On the other hand, sporadic BL is diagnosed outside of malaria-endemic areas, with only a minority of cases being EBV-positive (10-30%). This project seeks to generate high-throughput whole genome and transcriptome sequencing data from over 100 BL tumours in order to elucidate the genetic and molecular underpinnings of the disease. With this project, we aim to refine the mutational landscape of BL to facilitate the development of less toxic targeted therapies. We also plan on investigating the oncogenic role of EBV and whether it may serve as a better criterion for disease classification than the current system relying on geographic origin.

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Publications

Ryan Morin on Google Scholar