Morin lab

The Morin Laboratory performs cutting-edge lymphoma research by applying the latest molecular and computational methods in cancer genomics, developing and implementing highly sensitive molecular assays for monitoring circulating tumour DNA, and functionally validating our genomic findings using cell culture work and mouse xenograft models.

More information on the Morin lab is available here.

Projects

Comprehensive proteogenomic characterization of mantle cell lymphoma (MCL)

To more completely ascertain the mutations that lead to lymphomagenesis in Mantle cell lymphoma (MCL), Dr. Morin's laboratory is performing an integrative proteogenomic characterization of tumours using a combination of whole genome sequencing, RNA-seq and shotgun proteomics to identify novel coding and non-coding (i.e. regulatory) driver mutations that affect the natural history of MCL including treatment response.

Genetic and molecular mechanisms of treatment resistance in DLBCL

Using comprehensive genomic analyses and by integrating mutation and expression data from over 2000 diffuse large B-cell lymphoma (DLBCL) tumours, Dr. Morin's laboratory seeks 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.

Selected Publications

Evolutionary Conservation of Systemic and Reversible Amyloid Aggregation

Journal of Cell Science
Emma Lacroix, Lionel Pereira, Byoungjoo Yoo, Krysta M Coyle, Sahil Chandhok, Richard Zapf, Dane Marijan, Ryan D Morin, Stephanie Vlachos, Nicholas Harden, Timothy E Audas

In response to environmental stress, human cells have been shown to form reversible amyloid aggregates within the nucleus, termed amyloid bodies (A-bodies). These protective physiological structures share many of the biophysical characteristics associated with the pathological amyloids found in Alzheimer's and Parkinson's disease. Here, we show that A-bodies are evolutionarily conserved across the eukaryotic domain, with their detection in D. melanogaster and S. cerevisiae marking the first examples of these functional amyloids being induced outside of a cultured cell setting. The conditions triggering amyloidogenesis varied significantly among the species tested, with results indicating that A-body formation is a severe, but sub-lethal, stress response pathway that is tailored to an organism's environmental norms. RNA-sequencing analyses demonstrate that the regulatory low-complexity long non-coding RNAs that drive A-body aggregation are both conserved and essential in human, mouse, and chicken cells. Thus, the identification of these natural and reversible functional amyloids in a variety of evolutionarily diverse species, highlights the physiological significance of this protein conformation and will be informative in advancing our understanding of both functional and pathological amyloid aggregation events.

Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma

Blood Advances
Chiara Pighi, Taek-Chin Cheong, Mara Compagno, Enrico Patrucco, Maddalena Arigoni, Martina Olivero, Qi Wang, Cristina López, Stephan H Bernhart, Bruno M. Grande, Teresa Poggio, Fernanda Langellotto, Lisa Bonello, Riccardo Dall’Olio, Sandra Martínez-Martín, Luca Molinaro, Paola Franciadi Celle, Jonathan R Whitfield, Laura Soucek, Claudia Voena, Raffaele Calogero, Ryan D Morin, Louis M Staudt, Reiner Siebert, Alberto Zamò, Roberto Chiarle

The expression of BCL6 in B cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of Burkitt lymphoma (BL) patients. FBXO11 mutations impaired BCL6 degradation and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of either one or two copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B cell lymphoma onset, providing experimental evidence that FBXO11 is a haplo-insufficient oncosuppressor in B cell lymphoma. In WT and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degrader or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches such as BCL6 degraders and direct MYC inhibition could be exploited as a targeted therapy for BL.

Molecular profiling in diffuse large B-cell lymphoma: why so many types of subtypes?

British Journal of Haematology
Ryan D Morin, Sarah E Arthur, Daniel J Hodson

The term diffuse large B-cell lymphoma (DLBCL) includes a heterogeneous collection of biologically distinct tumours. This heterogeneity currently presents a barrier to the successful deployment of novel, biologically targeted therapies. Molecular profiling studies have recently proposed new molecular classification systems. These have the potential to resolve the biological heterogeneity of DLBCL into manageable subgroups of tumours that rely on shared oncogenic programmes. In many cases these biological programmes straddle the boundaries of our existing systems for classifying B-cell lymphomas. Here we review the findings from these major molecular profiling studies with a specific focus on those that propose new genetic subgroups of DLBCL. We highlight the areas of consensus and discordance between these studies and discuss the implications for current clinical practice and for clinical trials. Finally, we address the outstanding challenges and solutions to the introduction of genomic subtyping and precision medicine in DLBCL.

Prognostic significance of FCGR2B expression for the response of DLBCL patients to rituximab or obinutuzumab treatment

Blood Advances
Malgorzata Nowicka, Laura K Hilton, Margaret Ashton-Key, Chantal E Hargreaves, Chern Lee, Russell Foxall, Matthew J Carter, Stephen A Beers, Kathleen N Potter, Christopher R Bolen, Christian Klein, Andrea Knapp, Farheen Mir, Matthew Rose-Zerilli, Cathy Burton 0, Wolfram Klapper, David W Scott, Laurie H Sehn, Umberto Vitolo, Maurizio Martelli, Marek Trneny, Christopher K Rushton, Graham W Slack, Pedro Farinha, Jonathan C Strefford, Mikkel Z Oestergaard, Ryan D Morin, Mark S Cragg

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

Treating lymphoma is now a bit EZ-er

Blood Advances, 2021
Ryan D Morin, Sarah E Arthur, Sarit Assouline

Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase, the first of a multitude of epigenetic regulators that have been identified as recurrently mutated in FL and germinal center diffuse large B-cell lymphoma. In this review, we discuss the initial discovery and ongoing exploration of the functional role of EZH2 mutations in lymphomagenesis. We also explore the path from the preclinical development of tazemetostat to its approval for the treatment of relapsed FL, and potential future therapeutic applications. We discuss the clinical data that led to the approval of tazemetostat and ongoing research into the function of EZH2 and of tazemetostat in lymphomas that derive from the germinal center, which could increase the applicability of this drug in the future.

DNA-based species identification of ancient salmonid remains provides new insight into pre-contact Coast Salish salmon fisheries in Burrard Inlet, British Columbia, Canada

Journal of Archaeological Science: Reports
Jesse Morin, Hua Zhang, Thomas CA Royle, Camilla Speller, Miguel Alcaide, Ryan Morin, Dongya Yang

This study uses ancient DNA analysis to identify the species of salmonids from a number of pre-contact Coast Salish settlements in Burrard Inlet, Canada dating from about 390 BCE to CE 1600. Our results indicate that chum salmon (Oncorhynchus keta) dominates all Burrard Inlet zooarchaeological assemblages through time, followed distantly by pink salmon (Oncorhynchus gorbuscha), sockeye (Oncorhynchus nerka), coho (Oncorhynchus kisutch), and Chinook (Oncorhynchus tshawytscha), indicative of very stable local fisheries. These results indicate that the four well-sampled sites appear to have been occupied during the fall and winter and perhaps during the spring.

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Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma.

The Journal of pathology, 2019
Negri, Gian Luca, Grande, Bruno M, Delaidelli, Alberto, El-Naggar, Amal, Cochrane, Dawn, Lau, Ching C, Triche, Timothy J, Moore, Richard A, Jones, Steven Jm, Montpetit, Alexandre, Marra, Marco A, Malkin, David, Morin, Ryan D, Sorensen, Poul H
Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH.

Blood, 2019
Hilton, Laura K, Tang, Jeffrey, Ben-Neriah, Susana, Alcaide, Miguel, Jiang, Aixiang, Grande, Bruno M, Rushton, Christopher K, Boyle, Merrill, Meissner, Barbara, Scott, David W, Morin, Ryan D
High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/THs) include a group of diffuse large B-cell lymphomas (DLBCLs) with inferior outcomes after standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of germinal center B-cell DLBCLs (GCB-DLBCLs) as having a double-hit-like expression pattern (DHITsig) and inferior outcomes; however, only half of these cases have both MYC and BCL2 translocations identifiable using standard breakapart fluorescence in situ hybridization (FISH). Here, 20 DHITsig+ GCB-DLBCLs apparently lacking MYC and/or BCL2 rearrangements underwent whole-genome sequencing. This revealed 6 tumors with MYC or BCL2 rearrangements that were cryptic to breakapart FISH. Copy-number analysis identified 3 tumors with MYC and 6 tumors with MIR17HG gains or amplifications, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig+ tumors lacking MYC translocations; this may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/THs, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig+ DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes in GCB-DLBCL.

A Novel Multiplex Droplet Digital PCR Assay to Identify and Quantify KRAS Mutations in Clinical Specimens.

The Journal of molecular diagnostics : JMD, 2019
Alcaide, Miguel, Cheung, Matthew, Bushell, Kevin, Arthur, Sarah E, Wong, Hui-Li, Karasinska, Joanna, Renouf, Daniel, Schaeffer, David F, McNamara, Suzan, Tertre, Mathilde Couetoux du, Batist, Gerald, Kennecke, Hagen F, Karsan, Aly, Morin, Ryan D
Recurrent activating point mutations in KRAS are critical drivers in pancreatic cancer and have been attributed to resistance to anti-epidermal growth factor receptor therapy in colorectal cancer. Although KRAS genotyping provides limited clinical utility in the diagnosis and management of pancreatic cancer patients at present, inferences about the fractional abundance of KRAS mutations may inform on tumor purity in traditionally challenging clinical specimens and their potential use in precision medicine. KRAS genetic testing has indeed become an essential tool to guide treatment decisions in colorectal cancer, but an unmet need for methods standardization exists. Here, we present a unique droplet digital PCR method that enables the simultaneous detection and quantification of KRAS exon 2, 3, and 4 point mutations and copy number alterations. We have validated 13 mutations (G12S, G12R, G12D, G12A, G12V, G12C, G13D, G60V, Q61H, Q61L, A146V, A146T, and A146P) and focal KRAS amplifications by conducting this assay in a cohort of 100 DNA samples extracted from fresh frozen tumor biopsies, formaldehyde-fixed, paraffin-embedded tissue, and liquid biopsy specimens. Despite its modest lower limit of detection (approximately 1%), this assay will be a rapid cost-effective means to infer the purity of biopsy specimens carrying KRAS mutations and can be used in noninvasive serial monitoring of circulating tumor DNA to evaluate clinical response and/or detect early signs of relapse.

Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Blood, 2019
Grande, Bruno M, Gerhard, Daniela S, Jiang, Aixiang, Griner, Nicholas B, Abramson, Jeremy S, Alexander, Thomas B, Allen, Hilary, Ayers, Leona W, Bethony, Jeffrey M, Bhatia, Kishor, Bowen, Jay, Casper, Corey, Choi, John Kim, Culibrk, Luka, Davidsen, Tanja M, Dyer, Maureen A, Gastier-Foster, Julie M, Gesuwan, Patee, Greiner, Timothy C, Gross, Thomas G, Hanf, Benjamin, Harris, Nancy Lee, He, Yiwen, Irvin, John D, Jaffe, Elaine S, Jones, Steven J M, Kerchan, Patrick, Knoetze, Nicole, Leal, Fabio E, Lichtenberg, Tara M, Ma, Yussanne, Martin, Jean Paul, Martin, Marie-Reine, Mbulaiteye, Sam M, Mullighan, Charles G, Mungall, Andrew J, Namirembe, Constance, Novik, Karen, Noy, Ariela, Ogwang, Martin D, Omoding, Abraham, Orem, Jackson, Reynolds, Steven J, Rushton, Christopher K, Sandlund, John T, Schmitz, Roland, Taylor, Cynthia, Wilson, Wyndham H, Wright, George W, Zhao, Eric Y, Marra, Marco A, Morin, Ryan D, Staudt, Louis M
Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as , , and , we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Ultrasensitive Detection of Circulating Tumor DNA in Lymphoma via Targeted Hybridization Capture and Deep Sequencing of Barcoded Libraries.

Methods in molecular biology (Clifton, N.J.), 2019
Alcaide, Miguel, Rushton, Christopher, Morin, Ryan D
Liquid biopsies are rapidly emerging as powerful tools for the early detection of cancer, noninvasive genomic profiling of localized or metastatic tumors, prompt detection of treatment resistance-associated mutations, and monitoring of therapeutic response and minimal residual disease in patients during clinical follow-up. Growing evidence strongly supports the utility of circulating tumor DNA (ctDNA) as a biomarker for the stratification and clinical management of lymphoma patients. However, ctDNA is diluted by variable amounts of cell-free DNA (cfDNA) shed by nonneoplastic cells causing a background signal of wild-type DNA that limits the sensitivity of methods that rely on DNA sequencing. Here, we describe an error suppression method for single-molecule counting that relies on targeted sequencing of cfDNA libraries constructed with semi-degenerate barcode adapters. Custom pools of biotinylated DNA baits for target enrichment can be designed to specifically track somatic mutations in one patient, survey mutation hotspots with diagnostic and prognostic value or be comprised of comprehensive gene panels with broad patient coverage in lymphoma. Such methods are amenable to track ctDNA levels during longitudinal liquid biopsy testing with high specificity and sensitivity and characterize, in real time, the genetic profiles of tumors without the need of standard invasive biopsies. The analysis of ultra-deep sequencing data according to the bioinformatics pipelines also described in this chapter affords to harness lower limits of detection for ctDNA below 0.1%.

Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019
Ennishi, Daisuke, Jiang, Aixiang, Boyle, Merrill, Collinge, Brett, Grande, Bruno M, Ben-Neriah, Susana, Rushton, Christopher, Tang, Jeffrey, Thomas, Nicole, Slack, Graham W, Farinha, Pedro, Takata, Katsuyoshi, Miyata-Takata, Tomoko, Craig, Jeffrey, Mottok, Anja, Meissner, Barbara, Saberi, Saeed, Bashashati, Ali, Villa, Diego, Savage, Kerry J, Sehn, Laurie H, Kridel, Robert, Mungall, Andrew J, Marra, Marco A, Shah, Sohrab P, Steidl, Christian, Connors, Joseph M, Gascoyne, Randy D, Morin, Ryan D, Scott, David W
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.

Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma.

Nature communications, 2018
Arthur, Sarah E, Jiang, Aixiang, Grande, Bruno M, Alcaide, Miguel, Cojocaru, Razvan, Rushton, Christopher K, Mottok, Anja, Hilton, Laura K, Lat, Prince Kumar, Zhao, Eric Y, Culibrk, Luka, Ennishi, Daisuke, Jessa, Selin, Chong, Lauren, Thomas, Nicole, Pararajalingam, Prasath, Meissner, Barbara, Boyle, Merrill, Davidson, Jordan, Bushell, Kevin R, Lai, Daniel, Farinha, Pedro, Slack, Graham W, Morin, Gregg B, Shah, Sohrab, Sen, Dipankar, Jones, Steven J M, Mungall, Andrew J, Gascoyne, Randy D, Audas, Timothy E, Unrau, Peter, Marra, Marco A, Connors, Joseph M, Steidl, Christian, Scott, David W, Morin, Ryan D
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.

Nature, 2011
Morin, Ryan D, Mendez-Lago, Maria, Mungall, Andrew J, Goya, Rodrigo, Mungall, Karen L, Corbett, Richard D, Johnson, Nathalie A, Severson, Tesa M, Chiu, Readman, Field, Matthew, Jackman, Shaun, Krzywinski, Martin, Scott, David W, Trinh, Diane L, Tamura-Wells, Jessica, Li, Sa, Firme, Marlo R, Rogic, Sanja, Griffith, Malachi, Chan, Susanna, Yakovenko, Oleksandr, Meyer, Irmtraud M, Zhao, Eric Y, Smailus, Duane, Moksa, Michelle, Chittaranjan, Suganthi, Rimsza, Lisa, Brooks-Wilson, Angela, Spinelli, John J, Ben-Neriah, Susana, Meissner, Barbara, Woolcock, Bruce, Boyle, Merrill, McDonald, Helen, Tam, Angela, Zhao, Yongjun, Delaney, Allen, Zeng, Thomas, Tse, Kane, Butterfield, Yaron, Birol, Inanç, Holt, Rob, Schein, Jacqueline, Horsman, Douglas E, Moore, Richard, Jones, Steven J M, Connors, Joseph M, Hirst, Martin, Gascoyne, Randy D, Marra, Marco A
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.

Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.

Nature genetics, 2010
Morin, Ryan D, Johnson, Nathalie A, Severson, Tesa M, Mungall, Andrew J, An, Jianghong, Goya, Rodrigo, Paul, Jessica E, Boyle, Merrill, Woolcock, Bruce W, Kuchenbauer, Florian, Yap, Damian, Humphries, R Keith, Griffith, Obi L, Shah, Sohrab, Zhu, Henry, Kimbara, Michelle, Shashkin, Pavel, Charlot, Jean F, Tcherpakov, Marianna, Corbett, Richard, Tam, Angela, Varhol, Richard, Smailus, Duane, Moksa, Michelle, Zhao, Yongjun, Delaney, Allen, Qian, Hong, Birol, Inanc, Schein, Jacqueline, Moore, Richard, Holt, Robert, Horsman, Doug E, Connors, Joseph M, Jones, Steven, Aparicio, Samuel, Hirst, Martin, Gascoyne, Randy D, Marra, Marco A
Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.

Open Positions

Research Programmer, Ryan Morin Lab

Canada’s Michael Smith Genome Sciences Centre (GSC)

Today’s Research. Tomorrow’s Medicine.

The GSC is a department of the BC Cancer Research Institute and a high-throughput genome sequencing facility. We are leaders in genomics, proteomics and bioinformatics in pursuit of novel treatment strategies for cancers and other diseases.

Among the world’s first genome centres to be established within a cancer clinic, for more than two decades our scientists and innovators have been designing and deploying cutting-edge technologies to benefit health and advance clinical research.

Among the GSC’s most significant accomplishments are the first publication to demonstrate the use of whole-genome sequencing to inform cancer treatment planning, the first published sequence of the SARS coronavirus genome and major contributions to the first physical map of the human genome as part of the Human Genome Project.

By joining the GSC you will become part of an exceptional and diverse team of scientists, clinicians, experts and professionals operating at the leading edge of clinical research. We look for people who share our core values—science, timeliness, respect—to join us on our mission to use genome science for the betterment of health and society.

Job Reference No: RP_R00008_RDMorin Lab_2011_11_05

Job Summary

The Genome Sciences Centre at BC Cancer is looking for a highly motivated programmer with bioinformatics expertise to work in a fast-paced and highly rewarding research environment with a group of scientists and students who are at the bleeding edge of lymphoid cancer research. The successful candidate will work closely with all laboratories in the Centre for Lymphoid Cancer, namely Drs. David Scott, Christian Steidl, Leandro Venterutti and Ryan Morin. We are seeking a highly organized and motivated individual who will take a leadership role in conceptualizing, designing and implementing pipelines for standardizing and automating high-throughput analyses of cancer genome data. The position will support a growing diverse team including trainees and clinical researchers with expertise in bioinformatics, biostatistics and molecular biology. As a member of this group, you will be tasked with ongoing implementation, documentation, improvement, and testing of analytical tools and pipelines and will be required to follow best practices in software engineering. This will include ensuring proper handling, quality assurance and versioning of experimental data and metadata. You will also actively participate in routine code review and maintain robust version control of analytical pipelines using GitHub and continuous integration. As these pipelines typically begin with terabyte-scale inputs and require hundreds to thousands of concurrent processes, part of your job will involve ensuring efficient parallelization using a high-performance cluster with an emphasis on compatibility, reproducibility, ease of installation, and interoperability with various cloud-like computing environments. 

Organizational Status

Reports to Dr. Ryan Morin, Senior Scientist, Genome Sciences Centre and Bioinformatics Lead, Centre for Lymphoid Cancer. 

Specific Duties

As a scientific programmer you will work with our team members to:

  • Design, implement, and maintain pipelines for cancer genomic analyses based on the needs of the team, mostly using Snakemake, Python, and R
  • Suggest, and implement, improvements within our existing code base to increase efficiency and reduce the burden of large temporary files 
  • Design and implement testing suite to ensure robustness, scalability, and reproducibility of existing and new bioinformatic pipelines
  • Review pull requests and ensure internal and external contributors adhere to best practices and ensure compatibility with existing features
  • Assist trainees and staff with converting non-production code (R and Python) into reusable, documented, modular code 
  • Implement a testing framework using continuous integration to ensure the functionality of existing and new code is consistently maintained
  • Evaluate third-party software for new applications and integrate into new or existing pipelines
  • Build on existing databases and expand on existing application programming interfaces

Qualifications

  • Bachelor’s Degree in Computer Science completed

Required Skills:

  • 1+ years of Python programming experience and demonstrated track record in contributing to open-source software
  • Demonstrated proficiency in R (including tidyverse)
  • Excellent problem solving and troubleshooting skills
  • Organization and ability to produce results while maintaining multiple tasks
  • Experience developing software in a Linux or UNIX-like environment including shell scripting and common command-line tools
  • Experienced using Git for source control and willingness to assist a diverse team with its proper use
  • Demonstrated interpersonal skills including the ability to work effectively with others in a team environment

Preferred Skills:

  • Experience with basic Linux systems administration
  • Effective use of high-performance computing environment using the Slurm workload manager
  • Expertise with automated software testing
  • Package/dependency management expertise (e.g. conda) and/or experience with Docker, Singularity, or Kubernetes
  • Experience with mySQL or similar databases
  • Working knowledge of a combination of Awk and Perl and experience with databases would be beneficial

Application

Please submit a detailed cover letter and resume to bcgscjobs@bcgsc.ca, using Job Reference No: RP_R00008_RDMorin Lab_2011_11_05 in the subject line of your email.

This posting will remain online until filled.

Due to current COVID-19 restrictions, the position would require working remotely within British Columbia on a temporary basis with an ability to come to the normal workplace within reasonable notice. This restriction would be re-evaluated after finalization of reopening plans. As per the current Public Health Order, full vaccination against COVID-19 is a condition of employment with PHSA as of October 26, 2021.

We believe that equity, diversity and inclusivity are essential for the advancement of human knowledge and science.

We welcome all applicants and provide all employees with equal opportunity for advancement, regardless of race, colour, ancestry, place of origin, political belief, religion, marital status, family status, physical or mental disability, sex, sexual orientation, gender identity or expression, age, conviction of a criminal or summary conviction offence unrelated to their employment.

All qualified candidates are encouraged to apply; however, Canadian citizens and permanent residents will be given priority.

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