Dr. Marco Marra: Pioneer and Visionary in Cancer Genomics Research
Dr. Marco Marra is a highly distinguished genomics and bioinformatics researcher. He is the Director of Canada’s Michael Smith Genome Sciences Centre at the BC Cancer Agency and holds a faculty position at the University of British Columbia. The Centre is a state-of-the-art sequencing facility in Vancouver, Canada, with a major focus on the study of cancers. Many of their research projects are undertaken in collaborations with other Canadian and international institutions.
Dr. Marra and his laboratory participate in OCG’s Cancer Genome Characterization Initiative (CGCI) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET). For example, they have done extensive genomic analysis on non-Hodgkin lymphoma in CGCI, revealing a complex combination of recurrent mutations, including mutations in genes encoding epigenetic modifiers. The most recent findings from this study were published May 2013 in Blood1. For this issue of the OCG e-News, we spotlight Dr. Marra in an interview where he discusses his background in genome research, the key to the Centre’s success, and the challenges in relating genomic studies to treatment outcome.
What role did you play in the Human Genome Project?
The Genome Sequencing Center at Washington University in St. Louis, now known as The Genome Institute, was a major contributor to the sequencing of the human genome (Human Genome Project). I started my postdoctoral fellowship there in 1994 to begin sequencing the C. briggsae genome. Sequencing and assembling smaller genomes with better characterized gene functions allowed us to determine the right systems and tools needed to assemble the sequence of the human genome. Shortly after I started, I was asked by Dr. Waterston, my post-doctoral advisor, to develop and implement technologies to map the human genome and to sequence expressed sequence tags (ESTs). I, along with a team of scientists, used bacterial artificial chromosome (BAC) clones as the sequencing substrate for the human genome itself. The overlapping sequences from the BAC clones, together with the information from the ESTs, were used for the reconstruction and assembly of the whole genome.
Following your work on the human genome, you moved to Vancouver and eventually became Director of the Genome Sciences Centre. What makes the Centre successful in its mission to improve our understanding of the changes that occur in cancer and other disease genomes?
Our founding and continued philosophy is to go beyond creating an inventory of disease-specific alterations to understanding how those alterations affect underlying disease biology. To that end, we integrate informatics and biology in our laboratories. This integration allows us to complement efforts from other groups doing genomics research. Additionally, we are forward-thinking with our research objectives. We try to address the most pressing problems in cancer, such as “How do cancers become resistant to treatment?” and “Why are some cancers sensitive to treatment?” We’d like to understand how alterations in cancer genomes can provide answers. Much work has been done cataloging alterations in malignancies, but more work is needed to relate such catalogs of genetic alterations directly to treatment outcome. That is a hard problem that demands more than just the technology; it demands a strong interface with the clinic.
Does the Centre have infrastructure that connects laboratory and clinical research?
Yes. The centralized infrastructure of the British Columbia Cancer Agency (BCCA) facilitates the integration of cancer genomics with clinical research. The BCCA is a government entity that delivers cancer treatment and cancer control strategies to the population of British Columbia and captures information on all cancer diagnoses in the province (about 25,000 new cases of cancer annually). Approximately 19,000 of those cases are treated at a BCCA facility, enabling the collection of complete clinical information on each patient. This framework provides important research opportunities that connect genomic information to treatment and treatment outcomes.
How does the Centre keep up with the technological and informatics demands of cancer genomics research?
Well, it’s a bit of a struggle. Funds are scarce and technology advances rapidly. Depending on the cost, level of effort, and resources required, each new technology can either be additive or disruptive to our current technological infrastructure. As a result, we take a conservative, cost-effective approach to technology investment. We assess new instruments, and combine our assessments with those from our colleagues, to inform whether or not we systematically adopt a certain technology. Our aim isn’t to be at the absolute leading-edge of technology; it’s to use the best quality technology to do leading-edge clinically relevant genomics. We are able to accomplish this through our ability to successfully compete for financial support from organizations such as the National Cancer Institute the Canada Foundation for Innovation, and Genome Canada & Genome British Columbia, among other funders.
Recently your group integrated whole genome sequencing data with transcriptome data in non-Hodgkin lymphoma. What are the advantages of taking this type of multi–ome approach to cancer genome discovery?
A multi-ome approach provides an opportunity for a more detailed understanding of malignancies. As we’ve learned from our research in NHL, having multiple data types offers important clues to disease etiology that individually may be cryptic. Sequencing the whole genomes of NHL allowed us to detect novel relevant mutations and altered pathways (e.g. B-cell homing, which is linked to B-cell maturation) that were not identified by transcriptome or gene expression analyses alone. It also enabled a more accurate calculation of mutation prevalence in lymphomas. By combining transcriptome and whole genome data, we identified one of the most frequently mutated genes in follicular lymphoma. MLL2, a gene involved in histone modification, is inactivated in about 90% of follicular lymphomas (FL) and 30-60 % of diffuse large B-cell lymphomas (DLBCL). Frequent mutations in another histone modifying gene, EZH2, were also detected in both FL and DLBCL in our multi –ome analyses. These results suggest that MLL2 and EZH2 are fundamentally important in lymphoma biology, and they both play roles in regulating gene expression.
Taken together, sequencing transcriptomes and genomes led directly to the discovery that the epigenome may play a major role in lymphomas. Now we must interrogate the epigenome if we want a more complete understanding of how mutations like MLL2 and EZH2 are influencing the disease.
What are the underlying challenges of integrative analysis that your group has encountered in their study of NHL?
We need to understand how the NHL cancer genome evolves to help refine treatment strategies in the future. Presumably, the tumor’s environment influences the evolution of the disease, but we don’t know how. We also need to recognize in our sequencing analyses that there is no such thing as THE genome, even within a tumor sample. Tumors are a complex community of cells, which include individuals that have different genotypes and different biological properties. Thus, multiple samples from each tumor are likely to be more informative of biology than a single sample. Analysis of longitudinally collected samples, linked to treatment data, will inform on mechanisms and patterns of tumor evolution.
Understanding both tumor evolution and intra-tumoral genetic heterogeneity will help unravel some of the mysteries of treatment-resistant cancer. Treatment resistance can occur when a drug selects for resistant genotypes in a sub-population of cells in a tumor (it can also occur when a tumor does not respond to a particular treatment). What is the selective pressure applied by the treatment? What does the selective pressure act on? How can we avoid creating a treatment-resistant super-cancer? These are all pressing questions that we as researchers must answer in order to make a greater impact on patient outcomes.
To gain a deeper understanding of selective pressure exerted by treatment, we need better models of cancer progression under treatment and better strategies for sequencing analysis of tumors. Our current approach to sequencing analysis is to take a consensus view of genomic alterations at one point in time. This approach may not be all that relevant to treatment outcome, because it is not reflective of the genomic composition of the malignancy under selective pressure of treatment. A tumor’s genomic composition changes over time due to selection, high mutation rate, and other factors. This challenge must be addressed in future genomics studies.
References
- Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff R, Scott DW, Ding J, Roth A, Chiu R, Corbett RD, Chan FC, Mendez-Lago M, Trinh DL, et al.(2013) Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing. Blood 122(7):1256-65 (PMID: 23699601)