Marra lab

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.

Projects

Glioma-related projects

Staff: 

  • Susanna Chan 
  • Jungeun Song 

Trainees: 

  • 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 

Staff: 

  • Diane Trinh, MSc. 

Trainees: 

  • 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 

Trainees: 

  • 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

Alumni

  • 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.
  • Undergraduate researchers:
    • Ishika Luthra
    • Dianne Wu 
    • Alison Lee 
    • Jasmine Lin
    • Jess Paul
    • Pierre Cheung
    • Shaun Drummond
    • Eric Zhao
    • Sasha Maslova
    • Kevin C. Yang

Location

CRC

We are located at Canada's Michael Smith Genome Sciences Centre, part of the BC Cancer Research Centre.

Address: 
675 West 10th Avenue 
Vancouver, British Columbia
V5Z 1L3 

Projects

Selected Publications

Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes

Nature Cancer, 2020
Erin Pleasance, Emma Titmuss, Laura Williamson, Harwood Kwan, Luka Culibrk, Eric Y. Zhao, Katherine Dixon, Kevin Fan, Reanne Bowlby, Martin R. Jones, Yaoqing Shen, Jasleen K. Grewal, Jahanshah Ashkani, Kathleen Wee, Cameron J. Grisdale, My Linh Thibodeau, Zoltan Bozoky, Hillary Pearson, Elisa Majounie, Tariq Vira, Reva Shenwai, Karen L. Mungall, Eric Chuah, Anna Davies, Mya Warren, Caralyn Reisle, Melika Bonakdar, Gregory A. Taylor, Veronika Csizmok, Simon K. Chan, Zusheng Zong, Steve Bilobram, Amir Muhammadzadeh, Darryl D’Souza, Richard D. Corbett, Daniel MacMillan, Marcus Carreira, Caleb Choo, Dustin Bleile, Sara Sadeghi, Wei Zhang, Tina Wong, Dean Cheng, Scott D. Brown, Robert A. Holt, Richard A. Moore, Andrew J. Mungall, Yongjun Zhao, Jessica Nelson, Alexandra Fok, Yussanne Ma, Michael K. C. Lee, Jean-Michel Lavoie, Shehara Mendis, Joanna M. Karasinska, Balvir Deol, Ana Fisic, David F. Schaeffer, Stephen Yip, Kasmintan Schrader, Dean A. Regier, Deirdre Weymann, Stephen Chia, Karen Gelmon, Anna Tinker, Sophie Sun, Howard Lim, Daniel J. Renouf, Janessa Laskin, Steven J. M. Jones & Marco A. Marra

Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

Learn more.

Read our News Story about this publication here.

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration.

Cell reports, 2019
Chun, Hye-Jung E, Johann, Pascal D, Milne, Katy, Zapatka, Marc, Buellesbach, Annette, Ishaque, Naveed, Iskar, Murat, Erkek, Serap, Wei, Lisa, Tessier-Cloutier, Basile, Lever, Jake, Titmuss, Emma, Topham, James T, Bowlby, Reanne, Chuah, Eric, Mungall, Karen L, Ma, Yussanne, Mungall, Andrew J, Moore, Richard A, Taylor, Michael D, Gerhard, Daniela S, Jones, Steven J M, Korshunov, Andrey, Gessler, Manfred, Kerl, Kornelius, Hasselblatt, Martin, Frühwald, Michael C, Perlman, Elizabeth J, Nelson, Brad H, Pfister, Stefan M, Marra, Marco A, Kool, Marcel
Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.

Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments.

Proceedings of the National Academy of Sciences of the United States of America, 2019
Shen, Yaoqing, Grisdale, Cameron J, Islam, Sumaiya A, Bose, Pinaki, Lever, Jake, Zhao, Eric Y, Grinshtein, Natalie, Ma, Yussanne, Mungall, Andrew J, Moore, Richard A, Lun, Xueqing, Senger, Donna L, Robbins, Stephen M, Wang, Alice Yijun, MacIsaac, Julia L, Kobor, Michael S, Luchman, H Artee, Weiss, Samuel, Chan, Jennifer A, Blough, Michael D, Kaplan, David R, Cairncross, J Gregory, Marra, Marco A, Jones, Steven J M
Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.

The pivotal role of sampling recurrent tumors in the precision care of patients with tumors of the central nervous system.

Cold Spring Harbor molecular case studies, 2019
Wong, Derek, Shen, Yaoqing, Levine, Adrian B, Pleasance, Erin, Jones, Martin, Mungall, Karen, Thiessen, Brian, Toyota, Brian, Laskin, Janessa, Jones, Steven J M, Marra, Marco A, Yip, Stephen
Effective management of brain and spine tumors relies on a multidisciplinary approach encompassing surgery, radiation, and systemic therapy. In the era of personalized oncology, the latter is complemented by various molecularly targeting agents. Precise identification of cellular targets for these drugs requires comprehensive profiling of the cancer genome coupled with an efficient analytic pipeline, leading to an informed decision on drug selection, prognosis, and confirmation of the original pathological diagnosis. Acquisition of optimal tumor tissue for such analysis is paramount and often presents logistical challenges in neurosurgery. Here, we describe the experience and results of the Personalized OncoGenomics (POG) program with a focus on tumors of the central nervous system (CNS). Patients with recurrent CNS tumors were consented and enrolled into the POG program prior to accrual of tumor and matched blood followed by whole-genome and transcriptome sequencing and processing through the POG bioinformatic pipeline. Sixteen patients were enrolled into POG. In each case, POG analyses identified genomic drivers including novel oncogenic fusions, aberrant pathways, and putative therapeutic targets. POG has highlighted that personalized oncology is truly a multidisciplinary field, one in which neurosurgeons must play a vital role if these programs are to succeed and benefit our patients.

A high-throughput protocol for isolating cell-free circulating tumor DNA from peripheral blood.

BioTechniques, 2019
Pandoh, Pawan K, Corbett, Richard D, McDonald, Helen, Alcaide, Miguel, Kirk, Heather, Trinh, Eva, Haile, Simon, MacLeod, Tina, Smailus, Duane, Bilobram, Steve, Mungall, Andrew J, Ma, Yussanne, Moore, Richard A, Coope, Robin, Zhao, Yongjun, Jones, Steven Jm, Holt, Robert A, Karsan, Aly, Morin, Ryan D, Marra, Marco A
The analysis of cell-free circulating tumor DNA (ctDNA) is potentially a less invasive, more dynamic assessment of cancer progression and treatment response than characterizing solid tumor biopsies. Standard isolation methods require separation of plasma by centrifugation, a time-consuming step that complicates automation. To address these limitations, we present an automatable magnetic bead-based ctDNA isolation method that eliminates centrifugation to purify ctDNA directly from peripheral blood (PB). To develop and test our method, ctDNA from cancer patients was purified from PB and plasma. We found that allelic fractions of somatic single-nucleotide variants from target gene capture libraries were comparable, indicating that the PB ctDNA purification method may be a suitable replacement for the plasma-based protocols currently in use.

Evaluation of protocols for rRNA depletion-based RNA sequencing of nanogram inputs of mammalian total RNA.

PloS one, 2019
Haile, Simon, Corbett, Richard D, Bilobram, Steve, Mungall, Karen, Grande, Bruno M, Kirk, Heather, Pandoh, Pawan, MacLeod, Tina, McDonald, Helen, Bala, Miruna, Coope, Robin J, Moore, Richard A, Mungall, Andrew J, Zhao, Yongjun, Morin, Ryan D, Jones, Steven J, Marra, Marco A
Next generation RNA-sequencing (RNA-seq) is a flexible approach that can be applied to a range of applications including global quantification of transcript expression, the characterization of RNA structure such as splicing patterns and profiling of expressed mutations. Many RNA-seq protocols require up to microgram levels of total RNA input amounts to generate high quality data, and thus remain impractical for the limited starting material amounts typically obtained from rare cell populations, such as those from early developmental stages or from laser micro-dissected clinical samples. Here, we present an assessment of the contemporary ribosomal RNA depletion-based protocols, and identify those that are suitable for inputs as low as 1-10 ng of intact total RNA and 100-500 ng of partially degraded RNA from formalin-fixed paraffin-embedded tissues.

Whole-genome and transcriptome profiling of a metastatic thyroid-like follicular renal cell carcinoma.

Cold Spring Harbor molecular case studies, 2018
Ko, Jenny J, Grewal, Jasleen K, Ng, Tony, Lavoie, Jean-Michel, Thibodeau, My Linh, Shen, Yaoqing, Mungall, Andrew J, Taylor, Greg, Schrader, Kasmintan A, Jones, Steven J M, Kollmannsberger, Christian, Laskin, Janessa, Marra, Marco A
Thyroid-like follicular renal cell carcinoma (TLFRCC) is a rare cancer with few reports of metastatic disease. Little is known regarding genomic characteristics and therapeutic targets. We present the clinical, pathologic, genomic, and transcriptomic analyses of a case of a 27-yr-old male with TLFRCC who presented initially with bone metastases of unknown primary. Genomic DNA from peripheral blood and metastatic tumor samples were sequenced. A transcriptome of 280 million sequence reads was generated from the same tumor sample. Tumor somatic expression profiles were analyzed to detect aberrant expression. Genomic and transcriptomic data sets were integrated to reveal dysregulation in pathways and identify potential therapeutic targets. Integrative genomic analysis with The Cancer Genome Atlas (TCGA) data set revealed the following outliers in gene expression profiles: (81st percentile), (99th percentile), (100th percentile), and (99th and 100th percentiles, respectively), and (86th percentile). The patient received first-line sunitinib to target PDGFRA and PDGFRB and had stable disease for >6 mo, followed by nivolumab upon progression. To the authors' knowledge, this is the first reported case of comprehensive somatic genomic analyses in a patient with metastatic TLFRCC. Somatic analyses provided molecular confirmation of the primary site of cancer and potential therapeutic strategies in a rare disease with little evidence of efficacy on systemic therapy.

The clonal and mutational evolution spectrum of primary triple-negative breast cancers.

Nature, 2012
Shah, Sohrab P, Roth, Andrew, Goya, Rodrigo, Oloumi, Arusha, Ha, Gavin, Zhao, Yongjun, Turashvili, Gulisa, Ding, Jiarui, Tse, Kane, Haffari, Gholamreza, Bashashati, Ali, Prentice, Leah M, Khattra, Jaswinder, Burleigh, Angela, Yap, Damian, Bernard, Virginie, McPherson, Andrew, Shumansky, Karey, Crisan, Anamaria, Giuliany, Ryan, Heravi-Moussavi, Alireza, Rosner, Jamie, Lai, Daniel, Birol, Inanc, Varhol, Richard, Tam, Angela, Dhalla, Noreen, Zeng, Thomas, Ma, Kevin, Chan, Simon K, Griffith, Malachi, Moradian, Annie, Cheng, S-W Grace, Morin, Gregg B, Watson, Peter, Gelmon, Karen, Chia, Stephen, Chin, Suet-Feung, Curtis, Christina, Rueda, Oscar M, Pharoah, Paul D, Damaraju, Sambasivarao, Mackey, John, Hoon, Kelly, Harkins, Timothy, Tadigotla, Vasisht, Sigaroudinia, Mahvash, Gascard, Philippe, Tlsty, Thea, Costello, Joseph F, Meyer, Irmtraud M, Eaves, Connie J, Wasserman, Wyeth W, Jones, Steven, Huntsman, David, Hirst, Martin, Caldas, Carlos, Marra, Marco A, Aparicio, Samuel
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.

Genome biology, 2010
Jones, Steven Jm, Laskin, Janessa, Li, Yvonne Y, Griffith, Obi L, An, Jianghong, Bilenky, Mikhail, Butterfield, Yaron S, Cezard, Timothee, Chuah, Eric, Corbett, Richard, Fejes, Anthony P, Griffith, Malachi, Yee, John, Martin, Montgomery, Mayo, Michael, Melnyk, Nataliya, Morin, Ryan D, Pugh, Trevor J, Severson, Tesa, Shah, Sohrab P, Sutcliffe, Margaret, Tam, Angela, Terry, Jefferson, Thiessen, Nina, Thomson, Thomas, Varhol, Richard, Zeng, Thomas, Zhao, Yongjun, Moore, Richard A, Huntsman, David G, Birol, Inanc, Hirst, Martin, Holt, Robert A, Marra, Marco A
Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.

The Genome sequence of the SARS-associated coronavirus.

Science (New York, N.Y.), 2003
Marra, Marco A, Jones, Steven J M, Astell, Caroline R, Holt, Robert A, Brooks-Wilson, Angela, Butterfield, Yaron S N, Khattra, Jaswinder, Asano, Jennifer K, Barber, Sarah A, Chan, Susanna Y, Cloutier, Alison, Coughlin, Shaun M, Freeman, Doug, Girn, Noreen, Griffith, Obi L, Leach, Stephen R, Mayo, Michael, McDonald, Helen, Montgomery, Stephen B, Pandoh, Pawan K, Petrescu, Anca S, Robertson, A Gordon, Schein, Jacqueline E, Siddiqui, Asim, Smailus, Duane E, Stott, Jeff M, Yang, George S, Plummer, Francis, Andonov, Anton, Artsob, Harvey, Bastien, Nathalie, Bernard, Kathy, Booth, Timothy F, Bowness, Donnie, Czub, Martin, Drebot, Michael, Fernando, Lisa, Flick, Ramon, Garbutt, Michael, Gray, Michael, Grolla, Allen, Jones, Steven, Feldmann, Heinz, Meyers, Adrienne, Kabani, Amin, Li, Yan, Normand, Susan, Stroher, Ute, Tipples, Graham A, Tyler, Shaun, Vogrig, Robert, Ward, Diane, Watson, Brynn, Brunham, Robert C, Krajden, Mel, Petric, Martin, Skowronski, Danuta M, Upton, Chris, Roper, Rachel L
We sequenced the 29,751-base genome of the severe acute respiratory syndrome (SARS)-associated coronavirus known as the Tor2 isolate. The genome sequence reveals that this coronavirus is only moderately related to other known coronaviruses, including two human coronaviruses, HCoV-OC43 and HCoV-229E. Phylogenetic analysis of the predicted viral proteins indicates that the virus does not closely resemble any of the three previously known groups of coronaviruses. The genome sequence will aid in the diagnosis of SARS virus infection in humans and potential animal hosts (using polymerase chain reaction and immunological tests), in the development of antivirals (including neutralizing antibodies), and in the identification of putative epitopes for vaccine development.

Members

Faculty/Leaders

Staff

Susanna Chan

Assistant Production Coordinator

Richard Corbett

Process Development Coordinator

Lulu Crisostomo

Administrative Coordinator

Alessia Gagliardi

Staff Scientist

Martin Krzywinski

Staff Scientist

Karen Novik

Projects Team Leader

Diane Trinh

Staff Scientist

Post-Docs

Dan Jin

Post-Doctoral Fellow

Students/Trainees

Elizabeth Chun

Graduate Student

Dollina (Dolly) Dodani

Co-op Student

Veronique LeBlanc

Graduate Student

Stephen Lee

Graduate Student

Vanessa Porter

Graduate Student

Parsa Seyfourian

Student Volunteer

Yuka Takemon

Graduate Student

Lisa Wei

Graduate Student
Back to top