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.

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

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

Alessia Gagliardi

Staff Scientist

Joanne Johnson

Head, Project Management

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
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