Graduate students in the Marra lab are in the UBC Bioinformatics Training Program; UBC Genome Sciences and Technology Program (GSAT); and the UBC Medical Genetics Program. Trainees are working on characterizing cancer driver mutations and other alterations relevant to cancer, or on projects designed to identify and study critical cancer genes and pathways.
- Susanna Chan
- Jungeun Song
- Veronique LeBlanc, PhD Candidate
Glioblastomas (GBMs) account for nearly half of all primary malignant brain tumours, and current therapies are often only marginally effective. Our understanding of the underlying biology of these tumours and the development of new therapies have been complicated in part by widespread inter- and intratumoural heterogeneity. To explore this heterogeneity, we are performing regional subsampling of primary glioblastomas and organoids derived from these tissue samples. To identify cellular subpopulations within these tissues and organoids, we are performing single-cell RNA-sequencing (scRNA-seq) and genome sequencing on primary tumour samples and 1-3 matched organoids per sample. We have profiled samples from five tumour sets to date and have obtained sequencing data for 16,822 primary tissue cells and 11,043 organoid cells. Overall, our data will help evaluate the utility of tumour-derived organoids as model systems for GBM and will aid in identifying cellular subpopulations defined by gene expression patterns, both in primary GBM regional subsamples and their associated organoids. These analyses may also uncover novel therapeutic targets previously unrevealed through bulk analyses.
Ishikia Luthra, Co-op Student
Glioblastoma (GBM) is the most common and aggressive primary brain tumour, and is characterized by dismal patient outcomes. Such outcomes reveal (1) the lack of effective treatments for GBM patients; (2) the need for advances in our understanding of disease biology, and (3) the need for improved models to explore disease biology and drug development. To address these needs, we are studying patient derived organoids as models of GBM, using single cell sequencing to compare and contrast, at the DNA and RNA levels, genomic properties of tumor cells and organoid cells. Using software design and statistical analysis we develop high-throughput large-scale data pipelines to probe genomic heterogeneity across individual glioma- and patient-derived organoid cells. This heterogeneity is measured and quantified at both the DNA and RNA levels to: describe detailed intra- and inter- tumoral heterogeneity landscapes at the single cell level; assess the extent to which tumour heterogeneity is captured within organoids; capture observations of biological or therapeutic relevance.
Stephen Lee, PhD Candidate
CIC, or Capicua, encodes a transcriptional repressor that is itself repressed by RAS/MAPK signalling. CIC is a target of somatic mutation in 50-70% of type 1 low grade gliomas (LGG), with at least half of the alterations predicted to be deleterious. Type 1 LGGs are a cohort of tumours that are molecularly defined by the loss of heterozygosity of chromosome arms 1p and 19q and the presence of neomorphic IDH1/2 mutations. Despite the high frequency of mutations in CIC within this tumour type, CIC’s putative tumour suppressive role remains to be elucidated. It is also unclear how CIC may cooperate with neomorphic IDH1/2 to promote gliomagenesis. To comprehensively characterize the molecular consequences of CIC loss, we are performing RNA-seq, whole genome bisulfite sequencing, and ChIP-seq on isogenic CIC-wildtype (WT) and CIC-knockout (KO) normal human astrocytes, with and without IDH1 R132H mutations. Integrative analyses are ongoing to unveil the epigenetic mechanisms underpinning the regulatory changes in these isogenic cell line models.
Leukemia and lymphoma-related projects
- Diane Trinh, MSc.
- Dr. Alessia Gagliardi, Post-Doctoral Fellow
KMT2D / MLL2 is a SET domain containing protein that catalyses the methylation of lysine 4 on histone 3 (H3K4me) at enhancer regions, which marks active enhancers. KMT2D is frequently mutated in at least 27 different types of cancer, including the non-Hodgkins lymphomas (NHL) follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Many of these mutations are predicted to be inactivating, suggesting selective pressures favour loss of KMT2D function. We have generated knock out cell lines to model KMT2D loss of function and, using large scale cell-based screens, to look for synthetic lethal interactions with other loss-of function alterations across the genome.
Vanessa Porter, MSc., PhD Candidate
Genetic and epigenetic mutations have both been implicated to have a driving role in the development of cancer. The epigenetic regulator KMT2D is one of the most mutated genes across all cancers in TCGA, the cancer genome atlas. In particular, KMT2D loss-of-function mutations (LOF) are present in 90% of follicular lymphomas (FL) and 40% of diffuse large B cell lymphoma (DLBCL), indicating it may be an important tumour suppressor in non-Hodgkin lymphomas (NHL). KMT2D is a histone methyltransferase that deposits activating H3K4me1 marks on nucleosomes flanking enhancer regions. Our lab performed ChIP-sequencing analyses within human embryonic kidney cells (HEK293A) and showed that loss of KMT2D results in a decrease of H3K4me1 and H3K27ac marks at KMT2D-dependant active enhancers, resulting in decreased transcription of their target genes. A gene ontology analysis showed that genes affected by KMT2D loss were enriched within the retinoic acid and TGF-b pathways, while their promoter regions were enriched with DNA binding motifs corresponding to TGF-b signalling co-activator complex AP-1. We currently aim to validate these findings in other relevant cell types.
Lisa Wei, PhD Candidate
In paediatric AML, ~82% of patients with NUP98/NSD1 fusions also have FLT3/ITD, a known driver of treatment resistance. Patients with both genetic alterations had much lower rate of remission induction (27% vs 69% for FLT3/ITD patients with and without NUP98/NSD1, respectively) (Ostronoff et al. 2017). Although co-occurrence of these two events is associated with the low rate of response of patients to therapy, the mechanisms by which the co-expression of FLT3/ITD and NUP98/NSD1 induces innate treatment resistance is not well understood. We seek to understand such mechanisms, using RNA sequencing performed on 1,055 cases that were profiled as part of the AAML1031 clinical trial (Aplenc et al. 2016). We will infer transcription factor (TF) networks using regulatory network analysis and grouping co-expressed genes sharing common binding motifs of TFs, and attempt to comprehensively deduce the identity and consequences of dysregulated TF networks in treatment resistant paediatric AML.
Malignant rhabdoid tumour projects
- Elizabeth Chun, PhD Candidate
Malignant rhabdoid tumours (MRT) are aggressive pediatric solid cancers driven by loss of SMARCB1. To study deregulated transcriptional and epigenetic regulatory networks in MRT, we perform integrative bioinformatics analyses of whole genome, transcriptome, miRNA, genome-wide DNA methylation and histone modifications in primary patient tissues and cell lines. Our analyses have revealed molecular heterogeneity in MRT, and shown evidence for deregulated pathways underpinning MRT pathology.
Dr. Dan Jin, Post-Doctoral Fellow
Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers that frequently arise in the kidney and the brain. The overall survival rate is poor, due to the lack of effective treatments. Nearly all MRTs harbor loss of SMARCB1, which is a core subunit of the chromatin-remodeling SWI/SNF complex that plays an important role in epigenomic and transcriptomic regulation. We aim to understand the effect of SMARCB1 loss on chromatin structure and regulatory changes using genetic and epigenetic approaches
- Comprehensive and integrative analysis of the KMT2D regulome.
- James Topham, MSc. student.
- Bioinformatic approaches for identifying single nucleotide variants and profiling alternative expression in cancer transcriptomes.
- Dr. Rodrigo Goya, Ph.D. student.
- The MEF2B regulatory network.
- Dr. Julia Pon, MD / Ph.D. student.
- Generation and characterization of a lysine (K)-specific methyltransferase 2D knockout human cell line.
- Ryan Huff, M.Sc.
- The Regulatory Landscape of the Glioma-associated Transcription Factor Capicua.
- Marlo Firme, M.Sc.
- miRNA sequence analysis reveals cancer subtypes that correlate with tumour characteristics and patient outcomes.
- Dr. Emilia Lim, PhD student and Postdoctoral Fellow.
- Computational tools for CNV detection using probe-level analysis of Affymetrix SNP arrays: Application to the study of CNVs in follicular lymphoma.
- Dr. Noushin Farnoud, PhD student and Postdoctoral Fellow.
- Genomic studies of the normal and malignant neural crest.
- Dr. Olena Morozova, PhD student.
- Mutation discovery and characterization in lymphoid neoplasms using massively parallel RNA and DNA sequencing.
- Dr. Ryan Morin, MSc and PhD student.
- Biochemical characterization of FOXO1 mutations in lymphomas.
- Dr. Isabel Serrano, Postdoctoral Fellow.
- Massively parallel genomic sequencing for clinical identification of mutations that cause intellectual disability.
- Dr. Farah Zahir, Postdoctoral Fellow.
- The evolution of 5-FU drug resistance in colorectal cancer.
- Dr. Jill Mwenifumbo, Postdoctoral Fellow.
- Identification of MLL2 targets and synthetic lethal interactors.
- Dr. Maria Mendez-Lago, Postdoctoral Fellow.
- Bioinformatic analysis of cis-encoded antisense transcription.
- Dr. Sorana Morrissy, PhD student
- Methods for transcript variant discovery and alternative expression analysis - application to the study of fluorouracil resistance in colorectal cancer.
- Dr. Malachi Griffith, PhD student.
- Analysis of primary human cancers: from single genes to whole transcriptomes.
- Dr. Trevor Pugh, PhD student
- Cloning and annotation of novel transcripts from human embryonic stem cells.
- Jaswinder Khattra, MSc. student.
- Analysis of undifferentiated human embryonic stem cell lines using serial analysis of gene expression.
- Angelique Schnerch, MSc. student.
- A functional genomics approach identifies novel genes involved in steroid-hormone induced programmed cell death in Drosophila.
- Dr. Suganthi Chittaranjan PhD student, Co-Supervised with Sharon Gorski.
- Identification of echinus and characterization of its role in Drosophila eye development.
- Dr. Ian Bosdet, PhD student, Co-supervised with Sharon Gorski.
- Common regulators of apoptosis and autophagy-an analysis of known cell death genes in starvation induced autophagy.
- Dr. Claire Hou, PhD student co-supervised with Sharon Gorski.
- Undergraduate researchers:
- Ishika Luthra
- Dianne Wu
- Alison Lee
- Jasmine Lin
- Jess Paul
- Pierre Cheung
- Shaun Drummond
- Eric Zhao
- Sasha Maslova
- Kevin C. Yang
We are located at Canada's Michael Smith Genome Sciences Centre, part of the BC Cancer Research Centre.
675 West 10th Avenue
Vancouver, British Columbia