March 24, 2020

Teaming up to decode DNA damage repair

Ovarian and pancreatic cancer researchers join forces to debunk which treatments work for which patients

Ovarian and pancreatic cancer are some of the most challenging cancers to treat but their common characteristics have pointed to new treatments for certain subsets of patients. Drs. Stephanie Lheureux and Grainne O’Kane have teamed up to find out which patients can benefit from these new therapies.

Over the next year, with the support of an OICR Translational Research Initiative (TRI) Collaboration Award, Lheureux and O’Kane will be taking a deeper look into patient tumour samples that have a specific DNA damage repair deficiency, called homologous recombination deficiency (HRD). These tumours are thought to be sensitive – meaning, they can be eliminated – with a certain class of drugs called PARP inhibitors, but it is difficult to predict in the clinic whether a patients tumour has HRD or not. Further, it is difficult to determine whether a patient will benefit from using PARP inhibitors.

Lheureux, who is a medical oncologist specializing in ovarian cancers, and O’Kane, who is a medical oncologist specializing in pancreatic cancers, have set out to perform whole-genome analyses on patients with HRD to find a better way to identify which patients may respond to PARP inhibitors. Both researchers are excited to tap into each other’s expertise.

“Dr. Lheureux cares for many patients facing these challenges,” says O’Kane. “She has deep clinical expertise in this area.”

“Dr. O’Kane and her closest collaborators have excellent expertise in whole genome sequencing and bioinformatics,” says Lheureux. “We’re eager to work together.”

Their analyses may help them understand the biological mechanisms driving HRD and how HRD tumours become resistant to treatment. Their findings may also extend beyond ovarian and pancreatic cancers.

“We want to define the biological response to PARP inhibitors and the mechanism of resistance so that we can help these patients make the best treatment decisions for their specific disease,” says O’Kane.

“We’re motivated to redefine HRD and understand it on a deeper level to help us overcome resistance to treatment and extend the lives of those with these cancers,” says Lheureux.

Lheureux and O’Kane’s collaboration is supported by OICR’s TRI Collaboration Award, a pilot funding stream to support the training of young investigators and encourage collaboration amongst OICR’s TRI teams.

Learn more about OICR’s Pancreatic Cancer TRI, Ovarian Cancer TRI or read about the latest TRI News.

Image credit: Background vector created by pikisuperstar – www.freepik.com

March 24, 2020

The donations behind the discoveries: The Ontarians who made the Pan-Cancer Project possible

A technician at an Ontario Tumour Bank site at Kingston General Hospital works with frozen specimens.

The Pan-Cancer project made international headlines this month, but not without the contributions of thousands of individuals and the teams that preserve their specimens

In an unprecedented, decade-long study of whole cancer genomes, OICR researchers and collaborators have improved our fundamental understanding of the disease, indicating new directions for developing diagnostics and treatments. The Project was powered by 2,800 people with cancer who donated their biologic specimens to research. These contributions were facilitated and protected by groups such as the Ontario Tumour Bank (OTB).

From the operating room to the freezer

Many advances in cancer research, like those made by the Pan-Cancer Project, rely on hundreds – and sometimes thousands – of biospecimens. A patient’s donated blood, tumour and surrounding tissue may hold clues to future innovations in cancer diagnostics and therapies. But without biobanks – the repositories that collect and care for biological samples – the clues within these donations may never be discovered.

“Good science is built on good data and good omics data can only be drawn from well-preserved tissues,” says Monique Albert. “The advancements made by the Pan-Cancer Project would not have been possible without the diligent work of biobanking teams.”

Albert is the Director of OTB – a provincial bioresource operating in partnership with four state-of-the-art hospitals and cancer centres across Ontario. OTB plays a quiet but crucial role between the patient and the researcher, providing the fundamental biologic resources that research is built on.

Lowering the temperature and raising the bar

Day-to-day, biobanking teams – like OTB – work to implement the highest standards of preservation. From the operating room to the freezer and back to the lab, these teams tirelessly strive to maintain the quality of patient samples to inform cancer discoveries. OTB has held and raised leading biobanking standards for over 15 years.

“When The Cancer Genome Atlas started, biobanks around the world promised thousands of samples, but only a fraction of these samples were adequate for research,” says Albert, referring to Libraries of Flesh: The Sorry State of Human Tissue Storage. “This served as a wake-up call for the sector to unite, share best practices and set higher standards together.”

At the launch of The Cancer Genome Atlas (TCGA) in the early 2000s, OTB was up to – and in many ways exceeded – existing biobanking standards. This was thanks to the foresight of Dr. Brent Zanke and Sugy Kodeeswaran, who recognized the importance of stringent biobanking practices nearly a decade before biobanking became popularized.

As the only Canadian repository that was able to contribute to TCGA, OTB allowed hundreds of people from Ontario to contribute to this international initiative and to subsequent studies like the Pan-Cancer Project.

Since its inception, OTB has collected more than 185,000 samples donated by more than 21,000 individuals from across Ontario, enabling these donations to have a greater impact today and for years to come.

“Each sample represents a trace of an individual’s life, and we’re honoured to care for these valuable donations to science,” says Albert. “When they’re preserved properly, they become a lasting resource with infinite value. We’re proud that the donations from Ontario patients are paving the way for better and more targeted cancer treatment.”

OTB plays a critical role in leading the development of Canadian biobanking standards through the Canadian Tissue Repository Network (CTRNet), and biobanking standards around the world through the International Society for Biological and Environmental Repositories (ISBER).

Read more about OTB’s research resources and how OTB is collaborating to improve biobanking around the world by visiting their website at ontariotumourbank.ca.

March 12, 2020

The complexities of head and neck cancers may be simpler than we thought

Drs. Sampath Loganathan and Daniel Schramek.

Toronto-based research team uncovers dozens of rare mutations found in head and neck cancers converge on a single molecular pathway, amplifying the need to shut down this critical cancer-causing mechanism

With the advancement of DNA sequencing technology, researchers have discovered hundreds of genes that, when mutated, can drive cancer progression. Despite these discoveries, we don’t yet fully understand how the majority of cancer-causing genes work, leaving a large gap between the discovery of a gene mutation and the discovery of a new therapy. Dr. Daniel Schramek is filling that gap.

In a recent study, published in Science, Schramek and collaborators, including Dr. Trevor Pugh, Director of Genomics at OICR, analyzed the function of nearly 500 gene mutations found in head and neck cancers. Remarkably, they discovered that the many of these mutations affected one key molecular process within cancer cells. They shut down NOTCH signaling.

“While we see many different mutations in different genes across different patients, we found that many mutations, surprisingly, tend to do the same thing,” says Schramek, who is an investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute (LTRI). “This means the complexities of head and neck cancers may be simpler than we thought”

Schramek reasons that focusing on correcting the NOTCH pathway, rather than correcting the effects of each individual gene mutation, could simplify and focus the search for new and improved cancer therapies. He estimates that approximately 70 per cent of people with head and neck cancers have tumours that are affected by this pathway. Thus, a large majority of these patients could benefit from NOTCH-correcting cancer drugs.

“Every patient’s tumour is made up of different gene mutations and combinations of these mutations,” says Dr. Sampath Loganathan, first author of the study and Postdoctoral Fellow in the Schramek Lab. “Some of the more common, well-understood mutations are druggable – meaning they can be blocked with drugs – but there are hundreds of rarer, but important, mutations that we don’t yet understand.”

It is challenging to understand how a single mutation causes damage within a cell and ultimately leads to cancer. It is tremendously more challenging to understand the function of hundreds of mutations.


Our findings present a new way of thinking about precision oncology

Dr. Daniel Schramek

Schramek’s lab, however, developed an experimental system that allowed them to accelerate traditional functional testing for a fraction of the cost. Their system could test hundreds of gene mutations in a single mouse model. What would take several millions and decades in research and development, could now be done in one year for a fraction of the cost. Equipped with their powerful tools, this research group was the first to systematically look at rare mutations in head and neck cancers.

Schramek and collaborators are now working to identify key elements within the NOTCH pathway that can be blocked with chemicals. Their ultimate goal is to develop these chemicals into new drugs to help those with head, neck and other types of cancers. They will also continue to explore this phenomenon in other cancers such as breast and pancreatic cancers.

“Our findings present a new way of thinking about precision oncology,” Schramek says. “Instead of matching patients with specific mutations to specific treatments, researchers could focus on shutting down or restoring the pathways involved with those genes – hence, a pathway-centric model of precision oncology. We’re excited by this progress, and we look forward to bringing our ideas to future patients.”

This research was done in collaboration with OICR and was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute and the Human Frontier of Science Program. Schramek is a Kierans/Janigan Cancer Research Scientist and holds a Canada Research Chair in functional cancer genomics in the Department of Molecular Genetics at the University of Toronto.

Read more about this work in the Lunenfeld-Tanenbaum Research Institute’s news story.

March 12, 2020

Dr. Aaron Fenster named to the Order of Ontario

Dr. Aaron Fenster

OICR Imaging Program co-director, Dr. Aaron Fenster, awarded the province’s highest honour

OICR congratulates Dr. Aaron Fenster who was recently appointed to the Order of Ontario – the province’s highest honour.

The Order of Ontario recognizes individuals whose exceptional achievements have left a lasting legacy in the province, in Canada and beyond.

“Members of the Order of Ontario exemplify, individually and collectively, the best qualities of good citizenship,” said Her Honour Elizabeth Dowdeswell, Lieutenant Governor of Ontario. “Through their voluntary service, creativity, and the relentless pursuit of excellence, they demonstrate how we in Ontario are working to build a more just and sustainable future.”

Aaron Fenster and an imaging device prototype

In Fenster’s case, that means developing new medical imaging technologies and the infrastructure for new inventions to help more patients, sooner. Over four decades of medical imaging research and development, Fenster has invented dozens of new techniques, systems and devices that help scientists better understand cancer and clinicians deliver better treatment.

One of his systems for ultrasound image-guided prostate cancer treatment is in use around the world. Another one of his image-guided systems that could improve the accuracy of gynecologic cancer treatment is currently in clinical trials.

Fenster, who is a scientist at Robarts Research Institute and a professor at Western University, is well-recognized in the community for his commitment to translational research. For him, having the greatest impact on the health of patients requires collaboration across disciplines, industries and geographies to work on common challenges.


We work across disciplines like engineering, biology, physics and computer science, to design the best solutions. We work with clinicians, surgeons and radiologists to ensure these solutions can help patients. This is a special community.

Dr. Aaron Fenster

The programs Fenster has established, including OICR’s Imaging Program, have helped train the next generation of researchers who will continue to improve how we diagnose and treat cancers for years to come. Fenster’s imaging program in London – which he built from scratch – now includes more than 250 researchers and staff, including more than 100 graduate students.

“I am honoured to be named to the Order of Ontario,” Fenster said in an interview with the Schulich School of Medicine & Dentistry. “Although I will receive this honour, my staff and students deserve all the credit.”

The Lieutenant Governor bestowed the honour upon the newest Order of Ontario appointees during an investiture ceremony at Queen’s Park on March 11.

Read more about OICR’s Imaging Program or the latest Adaptive Oncology news.

March 2, 2020

Study reveals roots of leukemia that current chemotherapies can’t reach

John Dick

Researchers find the roots of leukemia relapse are present at diagnosis, uncovering clues to new treatment approaches

Despite significant advances in the treatment of acute lymphoblastic leukemia (ALL), the disease often returns aggressively in many patients after treatment. It is thought that current chemotherapies eliminate most leukemia cells, but groups of resistant cells may survive therapy, progress and eventually cause relapse. Dr. John Dick and collaborators have found these cells.

In a recent study published in Cancer Discovery, Dick and collaborators were able to identify and isolate groups of genetically distinct cells that drive ALL relapse.

The cells, termed diagnosis relapse initiating (dRI) clones were found to have genetic characteristics that differ from the other leukemia cells that are eliminated by treatment.

The study, along with a complementary study published in Blood Cancer Discovery, unraveled the genetic, epigenetic, metabolic and pro-survival molecular pathways driving treatment resistance. Together, these papers provide an integrated genomic and functional approach to describing the underlying genetics and mechanisms of relapse for ALL.

Interestingly, the research group discovered that dRI clones are present at diagnosis, opening opportunities to improve treatment up-front, devise drugs that target these resistant cells and prevent relapse from ever occurring.

Dr. Stephanie Dobson

“Our study has shown that genetic clones that contribute to disease recurrence already possess characteristics such as therapeutic tolerance that distinguish them from other clones at diagnosis,” says Dr. Stephanie Dobson, first author of the study who performed this research as a member of John Dick’s Lab. “Being able to isolate these clones at diagnosis, sometimes years prior to disease recurrence, has enabled us to begin to profile the properties allowing these particular cells to survive and act as reservoirs for relapse. This knowledge can be used to enhance our therapeutic approaches for targeting relapse and relapse-fated cells.”

“Xenografting added considerable new insight into the evolutionary fates and patterns of subclones obtained from diagnosis samples,” says John Dick, who is the co-senior author of the study, Senior Scientist at the Princess Margaret Cancer Centre and leader of OICR’s Acute Leukemia Translational Research Initiative. “We were able to gather extensive information about the genetics of the subclones from our models, which helped us describe the trajectories of each subclone and the order in which they acquired mutations.”

Ordering these mutations relied on the advanced machine learning algorithms designed by Dr. Quaid Morris and Jeff Wintersinger at the University of Toronto.

Research efforts are underway to build on these discoveries and determine how to block dRI clones.

The study was led by researchers at St. Jude Children’s Research Hospital, the Princess Margaret Cancer Centre and the University of Toronto and supported in part by OICR’s Acute Leukemia Translational Research Initiative.

This post has been adapted from the St. Jude Children’s Research Hospital news release.

February 27, 2020

Innovative drug screening method finds new promising molecules to treat aggressive lung cancers

Igor and Rima
Dr. Igor Stagljar (Photo by Sam Motala) | Dr. Rima Al-awar

International research group finds leukemia drugs and other small molecules may shrink treatment-resistant lung tumours

Lung cancer is the leading cause of cancer death in Canada and around the world. These fatal cancers often arise as a patient’s tumour cells acquire new mutations and become resistant to treatment but Dr. Igor Stagljar has found a new way to stop these tumours. In fact, he may have found four.

Stagljar’s research group at the University of Toronto is well-known for developing a live drug screening method – named MaMTH-DS – that can test potential cancer-fighting molecules in living cells. In a recent study published in Nature Chemical Biology, he and collaborators used these methods to focus on a common mutation, dubbed C797S, which often arises in lung cancers just months after initial treatment. The group identified four new compounds that could block the effects of C797S mutations with no effect on healthy cells.

“Our new technology allows us to find molecules that could be used against cancers for which no other treatment options are available,” says Stagljar, who is a professor of molecular genetics and biochemistry at the University of Toronto. “The advantage of our method is that we are doing it in living cells, where we have all the other molecular machineries present that are important for signal transduction. Also, the compounds are fished at very low dose, which allows us to test for both permeability and toxicity at the same time.”

Conventional drug screening strategies were not able to detect these compounds but Dr. Stagljar’s approach brought these new promising molecules to light.

Dr. Rima Al-awar

Two of the molecules identified have already been approved for patients with leukemia. Motivated by their recent findings, Stagljar and collaborators plan to evaluate the effects of these compounds in patients with lung cancer. The first clinical trial to evaluate one of these drugs – gilteritinib – is expected to launch later this year in Toronto, Canada and Zagreb, Croatia.

The other two molecules will require further research and development before they can be trialed in patients. One of these molecules, known as EMI1, could shut down the mutated cells in a completely new way, leveraging molecular machineries to degrade mutated proteins on the surface of tumour cells. The researchers think that EM1’s complex mechanism of action will make it more difficult for tumours to develop resistance to it.

Stagljar is working with Dr. Rima Al-awar, Head of Therapeutic Innovation and Drug Discovery at OICR, and her medicinal chemistry team to create an improved version of the EMI1 molecule. If proven successful, this molecule could potentially become a new treatment for the estimated 60,000 lung cancer patients worldwide who have the C797S mutation.

“Dr. Stagljar’s novel screening approach has identified these very promising molecules” says Al-awar. “We’re proud to collaborate with him and his group to further advance these molecules and accelerate the stages of experimentation between his discovery and helping those with the disease.”

Al-awar, whose drug discovery team recently brought a molecule for blood cancers into pre-clinical development, will leverage her group’s expertise to refine the molecule and move it into the next stage of development, where its ability to shrink tumours can be evaluated in experimental animal models and eventually patients.

This research was supported in part by the Consortium Québécois sur la Découverte du Médicament (CQDM), Cancer Research Society (CRS), Canadian Institute of Health Research (CIHR), Genome Canada and Ontario Research Fund. Stagljar was recently awarded a Prospects Oncology Fund grant from FACIT, OICR’s partner in commercialization, to develop a related drug screening platform, SIMPL.


This post has been adapted from the original announcement made by the University of Toronto Donnelly Centre.

February 26, 2020

How HER CODE CAMP aims to fix the diversity gap in computer science

OICR staff members Joanna Pineda, a Master’s Student, and Heather Gibling, a PhD Student, talk about how important it is to introduce young women, non-binary and transgender students to computer science.

February 25, 2020

Study shows common cell protein could be targeted to treat childhood brain cancers

Researchers discover that childhood brain cancer could be treated by blocking key cell-surface protein, pointing to a potential treatment approach with fewer toxic side effects

Michelle Francisco, first author, and Dr. Xi Huang, senior author

Chemotherapy for children with brain cancer is often toxic, leaving patients with serious life-long side effects but OICR-funded researchers have uncovered a new approach that may help.

In a study published in the Journal of Experimental Medicine, the Ontario-based research team discovered that blocking a specific protein on the surface of brain cancer cells can suppress the rampant growth of a tumour without harming the development of the brain.

The study focused on the protein CLIC1 in medulloblastoma, the most common type of childhood brain cancer. The group found that disrupting CLIC1 can halt medulloblastoma growth with very little effect on the developing brain in mice.

“Brain cancer is the leading cause of cancer-related death in children and young adults,” says Dr. Xi Huang, Scientist in the Developmental & Stem Cell Biology Program at The Hospital for Sick Children (SickKids) and senior author of the study. “We need new treatments to help these patients.”

We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases.

Michelle Francisco

CLIC1 belongs to a class of proteins called ion channels, which are important in the development of several other diseases like diabetes, epilepsy and high blood pressure. Many existing drugs and compounds act as ion channel modulators. The Huang Lab now has the high-throughput screening equipment to assess thousands of drug-like chemicals for those that can best block these ion channels.

“We believe our findings are significant because ion channels have been successfully targeted to treat numerous human diseases,” says Michelle Francisco, Research Project Coordinator in the Developmental & Stem Cell Biology Program at SickKids and first author of the study. “This helps pave the way between this discovery today and the impact it can have in the clinic.”

These findings build on Huang’s previous research on the potassium channel EAG2, which – like CLIC1 – is critical to medulloblastoma growth. In partnership with collaborators, Huang has shown that EAG2 could be blocked with an FDA-approved drug for schizophrenia to treat medulloblastoma in experimental mouse models and in a small patient study.

“We are fortunate to work with world-leading brain cancer researchers in Ontario,” Huang says, “We look forward to continuing our research to find new solutions for this devastating disease by targeting ion channels.”

This research was funded by OICR’s Brain Cancer Translational Research Initiative, SickKids Foundation, Arthur and Sonia Labatt Brain Tumour Research Centre, Garron Family Cancer Centre, b.r.a.i.n.child, Meagan’s Walk, Natural Sciences and Engineering Research Council (NSERC) Discovery Grant, U.S. Department of Defense (DoD) Peer Reviewed Cancer Research Program Career Development Award, Canadian Institute of Health Research (CIHR) Project Grants, and Sontag Foundation Distinguished Scientist Award to Xi Huang.

Read more about OICR’s brain cancer research.

February 18, 2020

Tackling brain cancer from all angles

Dr. Jüri Reimand

The Terry Fox Research Institute (TFRI) announced today that Dr. Jüri Reimand, OICR Investigator, has been granted the Terry Fox New Investigator Award to support his research into the evolution of glioblastoma, a deadly brain cancer that often recurs after treatment, with no long-term cure.

“This is a terrible disease with a dismal prognosis. It is usually fatal within a year or two after diagnosis and current therapies mostly fail to halt its recurrence and progress,” says Reimand. “We are taking a data-driven approach to see if we can change the tide on this disease by mapping the evolutionary history of each tumor and identifying genes and pathways that could be targeted through new or existing drugs.”

Backed by TFRI support, Reimand and collaborators are creating a robust multi-omics dataset derived from samples of glioblastoma tumours, including those that have returned after initial treatment. The dataset will incorporate many types of layered data from each sample including whole genome sequencing data, RNA sequencing data and proteomic data.

Reimand, who has expertise in integrating complex datasets, will develop machine learning strategies to identify new potential targets for treatment. The tools and methodologies will be designed to be applicable to other cancer types and will be made freely available for the research community to use.

“We hope that our expertise in computational biology can help shed new light on glioblastoma recurrence by analyzing tens of thousands of genes, proteins and RNAs in complex interaction networks, and ultimately provide a small number of high-confidence targets for further experimental work and therapy development,” said Reimand.

This research is enabled in large part by Reimand’s partnership with Dr. Sheila Singh, a clinician-scientist at McMaster University in Hamilton.

“We are routinely generating large amounts of complementary data utilizing different platforms that are difficult to compare,” says Dr. Singh. “This is why we are so excited to collaborate with Dr. Reimand to decipher GBM recurrence, as he brings invaluable expertise in computational biology, bioinformatics and machine learning. Dr. Reimand’s multi-omics integrative analysis will deliver our PPG with target genes, pathways and drug interactions that will help us to identify new therapies and understand the complex mechanisms of GBM recurrence.”

Read more about Dr. Jüri Reimand’s work.

This post has been adapted from the original announcement made by TFRI.

February 5, 2020

Unprecedented exploration generates most comprehensive map of cancer genomes charted to date

Pan-Cancer Project discovers causes of previously unexplained cancers, pinpoints cancer-causing events and zeroes in on mechanisms of development 

Toronto – (February 5, 2020) An international team has completed the most comprehensive study of whole cancer genomes to date, significantly improving our fundamental understanding of cancer and signposting new directions for its diagnosis and treatment.

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project (PCAWG), known as the Pan-Cancer Project, a collaboration involving more than 1,300 scientists and clinicians from 37 countries, analyzed more than 2,600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was then the launch-point for 16 working groups studying multiple aspects of cancer’s development, causation, progression and classification. 

Previous studies focused on the 1 per cent of the genome that codes for proteins, analogous to mapping the coasts of the continents. The Pan-Cancer Project explored in considerably greater detail the remaining 99 per cent of the genome, including key regions that control switching genes on and off — analogous to mapping the interiors of continents versus just their coastlines.

The Pan-Cancer Project has made available a comprehensive resource for cancer genomics research, including the raw genome sequencing data, software for cancer genome analysis, and multiple interactive websites exploring various aspects of the Pan-Cancer Project data.

The Pan-Cancer Project extended and advanced methods for analyzing cancer genomes which included cloud computing, and by applying these methods to its large dataset, discovered new knowledge about cancer biology and confirmed important findings of previous studies. In 23 papers published today in Nature and its affiliated journals, the Pan-Cancer Project reports that:

  • The cancer genome is finite and knowable, but enormously complicated. By combining sequencing of the whole cancer genome with a suite of analysis tools, we can characterize every genetic change found in a cancer, all the processes that have generated those mutations, and even the order of key events during a cancer’s life history.
  • Researchers are close to cataloguing all of the biological pathways involved in cancer and having a fuller picture of their actions in the genome. At least one causal mutation was found in virtually all of the cancers analyzed and the processes that generate mutations were found to be hugely diverse — from changes in single DNA letters to the reorganization of whole chromosomes. Multiple novel regions of the genome controlling how genes switch on and off were identified as targets of cancer-causing mutations.
  • Through a new method of “carbon dating, Pan-Cancer researchers discovered that it is possible to identify mutations which occurred years, sometimes even decades, before the tumour appears. This opens, theoretically, a window of opportunity for early cancer detection. 
  • Tumour types can be identified accurately according to the patterns of genetic changes seen throughout the genome, potentially aiding the diagnosis of a patient’s cancer where conventional clinical tests could not identify its type. Knowledge of the exact tumour type could also help tailor treatments.

“The incredible work of the Pan-Cancer Project team that was unveiled today is the culmination of a remarkable international collaboration that has enriched our understanding and provided new ways to approach the prevention, diagnosis and treatment of cancer,” said The Honourable Ross Romano, Ontario’s Minister of Colleges and Universities. “I congratulate the entire research group on this ground-breaking achievement in cancer research. Ontarians can be proud of the leading role OICR played in this initiative.”

“The findings we have shared with the world today are the culmination of an unparalleled, decade-long collaboration that explored the entire cancer genome,” says Dr. Lincoln Stein, member of the Project steering committee and Head of Adaptive Oncology at the Ontario Institute for Cancer Research (OICR). “With the knowledge we have gained about the origins and evolution of tumours, we can develop new tools to detect cancer earlier, develop more targeted therapies and treat patients more successfully.”

“The Pan-Cancer Project has generated a much-needed deeper understanding of the biology of cancer and how the elusive and untapped “dark matter” in the human genome drives cancer,” says Dr. Laszlo Radvanyi, OICR’s President and Scientific Director. “These discoveries can lead to totally new area of targets for cancer therapy. It is gratifying to know that OICR helped to lead the international effort, while also integrating a collaborative network of Ontario researchers to play a leading role in this global project. It is a further indication of the value of our strategic investments into data infrastructure, research and informatics expertise, as well as the value the Ontario government continues to create in supporting OICR. I congratulate Dr. Stein, his team and all Pan-Cancer researchers on this landmark achievement.”

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Backgrounder

More information

Nature landing page – https://www.nature.com/collections/pcawg/
ICGC – International Cancer Genome Consortium (https://icgc.org/)
TCGA – The Cancer Genome Atlas (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga)
PCAWG – PanCancer Analysis of Whole Genomes (dcc.icgc.org/pcawg)
UCSC – University of California Santa Cruz (pcawg.xenahubs.net)
Expression Atlas (www.ebi.ac.uk/gxa/home)
PCAWG-Scout (pcawgscout.bsc.es)
Chromothripsis Explorer (compbio.med.harvard.edu/chromothripsis)
COSMIC – Catalogue of Somatic Mutations in Cancer (https://cancer.sanger.ac.uk/cosmic)

About the Ontario Institute for Cancer Research

OICR is a collaborative, not-for-profit research institute funded by the Government of Ontario. We conduct and enable high-impact translational cancer research to accelerate the development of discoveries for patients around the world while maximizing the economic benefit of this research for the people of Ontario. For more information visit www.oicr.on.ca.

Media contact

Hal Costie
Ontario Institute for Cancer Research
647-260-7921
hal.costie@oicr.on.ca


Related links

February 5, 2020

New clues to cancer in the genome’s other 99 per cent

OICR leads more than 1,300 researchers from around the world in an unprecedented investigation into the dark matter of the human cancer genome.


Adapted from a story in OICR’s 2018-2019 Annual Report.


Three billion letters of code make up our complete genetic blueprint, yet everything we know about cancer to date comes from only one per cent of those letters.

What about the other 99 per cent? Could those regions be holding clues to new cancer solutions and cures? What could we find if we looked into this dark matter? Dr. Lincoln Stein wanted to find out – and he wasn’t alone.

In the fall of 2015, more than 1,300 investigators from the International Cancer Genome Consortium (ICGC) expressed interest in exploring these uncharted regions. Four years and hundreds of terabytes of data analysis later, they’ve found ways to map the evolutionary history of cancer, identified traces of the disease long before it is diagnosed, and elevated the world’s standards for genomics data sharing and research.

A collective goal, a collaborative feat

Jennifer Jennings

“When this project was first announced, we were delighted by the overwhelming interest,” says Jennifer Jennings, Senior Project Manager of the ICGC. She says that was when the scientific leadership of ICGC realized that a concerted effort was needed to address common computational and logistical challenges, leverage the strengths of collaborators and develop shared infrastructure to achieve the ultimate goals of this research.

They named this project PCAWG, the Pan-Cancer Analysis of Whole Genomes Project, also known as the Pan-Cancer Project , which would soon become the largest ever pan-cancer analysis of whole genomes and one of the largest coordinated cancer research endeavors to date.

Stein and a small group of scientific leaders took on the challenge of synchronizing research groups with similar research goals, strategically rearranging expertise and coordinating collaboration on an international scale.

“Organizing and bringing these researchers together was the greatest challenge,” says Stein, who is the Head of Adaptive Oncology at OICR. “Working with others may be slower at first and the benefits aren’t always evident, but the rigour of the resulting science and the progress made is greater than what any of us could do on our own.”

Turning data into discoveries

Dr.Lincoln Stein

PCAWG researchers went on to investigate more than 2,600 cancer whole genomes from ICGC patient donors across more than 20 primary disease sites such as the pancreas and the brain. They created the computational tools and established the necessary infrastructure to process and analyze more than 800 terabytes of genomic data in a standardized, accurate and timely fashion.

Powered by these tools, they were able to order the progression of genetic changes that lead to certain types of cancer and showed that these events may occur decades before diagnosis.

“For exceptional cases like in certain ovarian cancers, we were able to see these early events happening 10 to 20 years before the patient has any symptoms,” says Stein. “This opens up a much larger window of opportunity for earlier detection and treatment than we thought possible.”

Understanding the order of genetic changes that lead to cancer – or the probability that one will occur after another – may allow researchers to outsmart how a tumour evolves. This knowledge could help devise new strategies to treat these changes as they occur or prevent them from occurring in the first place, Stein says.

PCAWG researchers have also discovered common patterns in the distribution of genetic mutations that may point to new causes of cancer. Similar to the common genetic signatures associated with smoking and ultraviolet radiation, these patterns may point to unknown environmental or behavioural causes that, once fully understood, could be used to change course and help prevent cancer.

“The biological insights discovered through PCAWG have tremendously advanced our understanding of cancer genomics and we’re approaching a place where we know all the molecular pathways involved with cancer,” says Stein. “We’ve discovered the causes of two thirds of cancers that were previously unexplained — but this is just the beginning.”

Setting new standards for the future

Last July, PCAWG data were officially made available for the scientific community to use as a resource for future cancer research. The key PCAWG findings were recently published in a collection of more than 20 scholarly papers in Nature and its affiliated journals. An expected 40 additional papers relying on PCAWG data will be published within the next year alone.

PCAWG methodologies are now the world’s gold standard for whole genome data processing and analysis. They will continue to be used for years to come as more patient samples are collected and sequenced around the world. All related computational tools, including the data exploration and discovery tools, have been made publicly available.

“We made both the genomic data, and the computational pipelines to analyze it, free to use for the global cancer research community,” says Stein. “Now, others can analyze these data – or new data – at the same level as we have in the pursuit of new cancer research discoveries.”


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February 5, 2020

AI algorithm classifies cancer types better than experts

Gurnit Atwal and Wei Jiao

Pan-Cancer Project researchers develop deep learning system that can determine where a cancer originates with better accuracy than human experts

If doctors know where a patient’s cancer started, they can better treat the disease. Unfortunately, this is not always possible, but AI could play a role in solving that.

In a study published today in Nature Communications, a Toronto-based researcher group developed a deep learning system that can accurately classify cancers and identify where they originated based on patterns in their DNA. The system could potentially help clinicians differentiate difficult-to-classify tumours and help recommend the most appropriate treatment option for their patients.

“We reasoned that there was something within the cancer’s DNA that could help us classify these tumours,” says Dr. Quaid Morris, OICR Senior Investigator and co-lead author of the study1. “But I didn’t expect our system to work at well as it does – in some cases, far better than pathologists.”

The team

The initiative began with the dataset: 2,600 whole genomes across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes Project, also known as the Pan-Cancer Project or PCAWG.

Dr. Lincoln Stein, Head, Adaptive Oncology at OICR and member of the Pan-Cancer Project Steering Committee, and his team began to work with these data to identify patterns in a cancer’s genetic material that could help classify these tumours. To them, this was a perfect problem for AI.

When we started to collaborate, We realized we had something amazing.
– Wei Jiao

“Deep learning models excel when they’re trained on large amounts of data,” says Wei Jiao, Research Associate in the Stein Lab and co-first author of the study. “We had an incredibly large dataset to work with, the most comprehensive dataset of whole cancer genomes to date, but we also needed the machine learning expertise.”

The Stein Lab posted their progress on bioRxiv, an open-access repository for biology publications that have not yet been peer-reviewed, which in turn sparked the collaboration between his team and the Morris Lab – a group with deep machine learning expertise.

The system

The development of their deep learning system was not simple. They mined through terabytes of data looking for patterns in the type of mutations, the source of mutations and where mutations occurred in the genome, among other factors.

To their surprise, they found that patterns in driver mutations – the changes in DNA that are thought to ‘drive’ the development of cancer – were not useful in determining where the tumour originated. Instead, they found that patterns in the distribution of mutations and the type of mutation within a patient’s sample could better classify the patient’s disease.

“We knew that we could distinguish between two different types of healthy cells by looking at how the DNA within the cell types are packaged,” says Stein, who is a co-lead author of the study. “We were surprised and gratified that we could do the same using cancer cells.”

“We saw that the tightly-packaged sections – also known as the closed chromatin – would have many more mutations than the loosely wound sections,” says Gurnit Atwal, PhD Candidate in the Morris Lab and co-first author of the study. “It was like the normal cell was casting a shadow on the cancer cell, and we just had to read the shadows.”

To achieve the highest accuracy, the research group developed a deep learning neural network-based system, a type of system that is loosely modeled after the human brain and commonly used to recognize patterns in images, audio and text. Their system achieved an accuracy of 91 per cent – roughly double the accuracy that trained pathologists can achieve using traditional methods when presented with a primary tumour and no clinical information.

Further, they tested their model on an additional 2,000 tumours from patients in the Netherlands who donated their cancer genomic data to the Hartwig Medical Foundation and the system still performed with a remarkably high level of accuracy.

 “As more cancer genomes are sequenced, we can gain the ability to classify rarer cancers,” says Atwal. “Where we are now is great, but there is more work to be done.”

The potential

This study presents a deep learning system that could potentially improve how cancers are classified, enhancing the accuracy of current diagnostic tests and the treatment decisions they inform.

For some patients, this system could tell them where their cancer began, giving them valuable information about which course of treatment to choose. The system also could serve as a tool to help doctors identify whether a tumour in a patient who has been treated for cancer in the past is an entirely new tumour or a recurring tumour that has spread.

“A treatment plan for a cancer that originated in the throat may be very different than one for that originated in the breast, and the treatment for a cancer that has returned is different than for one that has metastasized,” says Atwal. “One day, our tool could help give doctors the power to distinguish these classes of tumours, giving patients valuable information that wouldn’t have been available otherwise.”

The authors of the study suggest that their system could start helping patients soon. They plan to further refine their system for patients with rare cancers before moving towards clinical studies. 

“The potential impact of the system we’ve developed is encouraging,” says Morris. “We look forward to turning this system into a tool that can help clinicians and future cancer patients tackle this disease.”


1Morris is also a Canada CIFAR AI Chair, Faculty Member at the Vector Institute, and Professor at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research.


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