February 5, 2020

Whole-genome analysis generates new insights into viruses involved in cancer

Dr. Ivan Borozan

OICR researchers scan more than 2,600 whole cancer genomes for traces of known and potentially unknown cancer-causing viruses, identifying new ways that these pathogens may eventually lead to the disease

It is estimated that viruses cause nearly 10 per cent of all cancers. These cancer-causing viruses – also known as oncoviruses – can make changes to normal cells that may eventually lead to the disease. As researchers better understand how oncoviruses cause cancer, they can develop new therapies and vaccines to prevent them from doing so.

In the most extensive exploration of cancer genomes to date, OICR researchers and collaborators discovered new insights into the mechanisms behind the seven known oncoviruses, and provided strong evidence that there are no other human cancer-causing viruses in existence.

Their study was published today in Nature Genetics, alongside more than 20 related publications from the Pan-Cancer Analysis of Whole Genomes Project, also known as the Pan-Cancer Project or PCAWG. The research group analyzed whole genome data from more than 2,600 patient tumours representing 35 different tumour types.

“The Pan-Cancer Project is one of the largest cancer genome projects to date,” says Dr. Ivan Borozan, Scientific Associate at OICR and leading co-author of the study. “This project allowed us to search for viruses in the most comprehensive collection of cancer genomes using the latest and most advanced techniques. To analyze this extensive dataset, we first had to develop computational tools and analysis pipelines that can efficiently process large-scale sequencing data and – at the same time – extract accurate information about minute amounts of the viral genome present in each individual sample. The results generated using these tools were then integrated to decipher molecular mechanisms that lead to the development of cancer.”

Our research points towards a future where these cancers can be treated more effectively, and potentially prevented in the first place.
– Dr. Ivan Borozan

The group discovered that an individual’s immune system, while trying to protect itself from a certain strain of the well-known human papillomavirus (HPV), may cause damage to normal DNA that lead to the development of bladder, head, neck and cervical cancers.

The study also found that the hepatitis B virus (HBV), which is linked to some liver cancers, causes damage in normal cells by integrating into human DNA close to TERT, a well-understood cancer-driving gene.

Spinoffs of this research initiative have led to important discoveries about the Epstein-Barr Virus (EBV) and how it can promote the development of stomach cancer.

“These findings can help us develop new vaccines or therapies that target these mechanisms,” says Borozan. “Our research points towards a future where these cancers can be treated more effectively, and potentially prevented in the first place.”

As new sequencing research initiatives emerge, the research group’s computational tools and pipelines – which are available for the research community to use – will help further explain the mechanisms behind this complex disease.

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February 5, 2020

Dr. Lincoln Stein talks about the Pan-Cancer Project

An overview of the Pan-Cancer Project with Dr. Lincoln Stein.

Watch more Pan-Cancer Project videos

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February 5, 2020

Backgrounder: Pan-Cancer Project

Supplementary information about the news release: Unprecedented exploration generates most comprehensive map of cancer genomes charted to date 

Overview of the Pan-Cancer Project

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG), known as the Pan-Cancer Project, is an international collaboration to identify common patterns of mutation in more than 2,600 whole cancer genomes from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). It builds upon the previous work of those initiatives, which predominantly concentrated on the regions of the genome that code for proteins.

Researchers aim to understand the genomic changes in many forms of cancer worldwide, with a view to enabling further research into causes, prevention, diagnosis and treatment of cancers.

The Pan-Cancer Project has explored the nature and consequences of DNA variations in cancer, across the entire genome, from both protein-coding genes and from areas of DNA that do not code for proteins. The Pan-Cancer Project is the most comprehensive analysis of the non-coding regions of cancer genomes performed to date.

DNA changes can be inherited (germline) or appear during a person’s life (somatic), and the Pan-Cancer Project is investigating both types of these variations in DNA of cancer cells, looking at areas involved in regulating genes, sites for non-coding RNA and large-scale structural rearrangements in the genome.

Why was the ICGC/TCGA Pan-Cancer Project needed?

This is the largest, most comprehensive analysis of cancer genomes to date.  To understand the complex changes in the genome, a huge amount of data was needed. This was only achieved through working collaboratively and sharing data. The project analysed almost every cancer genome throughout the world that was publically available at the start of the project.

What is the main finding from the Pan-Cancer Project?

The main point is 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, it is possible to highlight and describe every genetic change found in a cancer. These include all the processes that have generated those mutations, the biochemical pathways in the cells that are affected by these genetic changes, the kinds of cells that were originally transformed from normal to cancerous, and even the order of key events during a cancer’s life history.

How will this help cancer research?

The Pan-Cancer researchers have provided comprehensive insights into many aspects of cancer genomes. Previous work had documented some of these features in some tumour types, but here, on the same, large international cohort of patients across all the common tumour types, all these aspects have been analysed together. This provides a more comprehensive, more uniform map of the cancer genome than the earlier snapshots had provided.

The ICGC/TCGA Pan-Cancer Project researchers have established an enormous resource for the scientific community to use, a resource that will underpin ongoing development of analysis methods, provide a testing ground for new ideas about cancer development and act as a benchmark for comparison of future sequencing studies.

Pan-Cancer Project data is available to the research community, and will help accelerate additional discoveries. Over time, these discoveries will lead to improved detection, management and treatment of cancer.

Cancer genomes are complex, and much more data, potentially in thousands to tens of thousands of patients per tumour type, are needed to fully understand them – this is why shared data and resources like the Pan-Cancer Project are so important.

The suite of analysis tools generated by the project has been also released to the scientific and clinical communities, and is free to be used and further developed. This is important because data analysis has been a major barrier to improving access to cancer genome sequencing. The raw sequencing data and downstream analytical results are also released to the community under appropriate controls to safeguard participants’ privacy.

How will the Pan-Cancer Project help cancer patients?

The study will enable more personalised medicine in the future, once clinical whole genome sequencing of a patient’s cancer becomes more widely adopted. This will include accurate diagnosis of tumour type, better prediction of clinical outcome, and choice of the optimal treatment for the patient.

The Pan-Cancer researchers have developed a method to find out where cancers come from (find the ‘cell of origin’) in patients in whom this wasn’t possible to identify using standard diagnostic techniques. This could impact diagnosis and treatment in the future.

Due to the study, researchers can now carbon-date cancers, and identify the age of tumours and the key genomic stages they pass through. This has helped us identify what the earliest changes are in the evolution of many cancer types, with the potential to develop new strategies for diagnosing or intervening in tumours at earlier stages. We are not there yet, but this would be the goal.

By looking at the 99% of the cancer genome that was previously invisible – the part that doesn’t code for proteins – the study filled in gaps in our knowledge of what drives cancer. At least one causative genetic change was found in more than 95% of all cancers in the study, and many individual tumours had 5-10 or more causative mutations identified. This information will help us find better methods for diagnosis, because the causative mutations inform what type of tumour developed, and better drugs, because the causative mutations may suggest useful drug targets. A future goal, begun in the Pan-Cancer Project, is to be able to identify for any given patient in clinic all of the specific mutations that drive his or her cancer.

Researchers described many new processes generating mutations in cancer genomes. These processes leave distinctive ‘mutational signatures’ in the genome, and these signatures can give clues as to what may have caused the cancer. For example, lifestyle exposures such as cigarette smoking and sun-bathing can cause patterns of mutation that are highly distinctive; likewise, inherited cancer disorders can lead to distinctive signatures. These signatures can be read from a patient’s cancer genome, and then compared against the compendium of signatures generated in this study.

What else has the Pan-Cancer Project revealed?

  • By combining data on coding and non-coding cancer-causing genetic changes, at least one mutation that caused cancer was found in virtually all (95%) of the cancers analyzed, with most patients’ tumours having a handful of genetic causal events identified. This suggests that we are close to the goal of cataloguing all of the biological pathways involved in cancer.
  • Revealed new “roads leading to Rome” that may provide avenues for treatment. Cancers use various ways to activate pathways that lead to tumours (oncogenic pathways). The Pan-Cancer Project study has mapped out additional routes involving structure, transcription, and driver mutations in the non-coding parts of the genome for a comprehensive set of tumour types.
  • There is massive complexity in how the cancer cell interprets the genome. Different genetic changes in the DNA can lead to extensive variability in the RNA transcription undertaken by the cell, which is the first level of a cell’s interpretation of the genome. Many of these RNA changes are important first messages instructing the cell to behave like a cancer cell.
  • The processes that generate mutations in cancer genomes are hugely diverse, with more than 80 different patterns of mutation, ranging from changes affecting single DNA letters to large-scale reorganisation of whole chromosomes.
  • Many specialised regions of the genome are disrupted in cancers compared to normal cells, including DNA in mitochondria, the power-houses of cells; telomeres, which cap the ends of chromosomes; repetitive DNA sequences, which can reactivate and multiply in a tumour’s genome; and virus genomes, which can insert nearby particular cancer genes.

Data resources – how people can access the data

Pan-Cancer project researchers established an enormous resource for the scientific community to use, enabling a wider and deeper exploration of the cancer genome, by making sequencing data on genomes’ non-coding regions available and providing tools to examine this data. It is expected that the availability of this resource will lead to further discoveries and help researchers improve the detection, management and treatment of cancer.

  • Open-tier data can be viewed at https://dcc.icgc.org/
  • Detailed instructions for obtaining access to the controlled-tier PCAWG data can be found in the DCC PCAWG documentation pages (https://docs.icgc.org/pcawg/data/).
  • Researchers can contact dcc-support@icgc.org if they have inquiries about data access.

Next steps

Further insights into cancer biology are expected to be made using the Pan-Cancer data and related software tools that have been made available to the global cancer research community.

In 2015, the ICGC, in response to the realization of the potential of genomics in healthcare, released a position “white paper” on the evolution of ICGC into more directly impacting on human health. Emanating from the ICGC for Medicine (ICGCmed) white paper is ICGC’s next project which aims to Accelerate Research in Genomic Oncology (The ARGO Project), where key clinical questions and patient clinical data drive the interrogation of cancer genomes. More information can be found at https://icgc-argo.org/.

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February 5, 2020

Finding the roots of cancer, ‘It’s a needle in a haystack’

Dr. Shimin Shuai

OICR’s Dr. Shimin Shuai and Pan-Cancer Project collaborators identify new cancer-causing mutations in the non-coding region of the cancer genome

Cancer begins with a ‘driver’ mutation – a DNA abnormality that may cause mutations to accumulate and give rise to the disease. These mutations are key targets for cancer therapies but most research to date has focused on the driver mutations within a small portion of the genome – the one per cent of our DNA that codes for proteins.

Now, researchers from the Pan-Cancer Project have explored the other 99 per cent.

In their paper, published today in Nature, the research team detailed a new set of potential driver mutations within the vast non-coding regions of the human genome. These driver mutations could point to new therapeutic approaches or new ways to personalize cancer treatment decisions in the future. The group’s analysis confirms previously reported drivers and raises doubts about others.

It’s amazing that we can use computational tools and algorithms to find important clues that direct us towards a future where precision medicine is a reality.
– Dr. Shimin Shuai

“We looked into the whole genomes of nearly 2,600 patients and some samples had tens of thousands of mutations,” says Dr. Shimin Shuai, leader of OICR’s contribution to the Pan-Cancer Project driver working group. “Driver mutations are really rare in the non-coding regions of the genome so we needed to design computational tools to find a needle in a haystack.”

A key tool behind these discoveries was a computational algorithm called DriverPower, developed by Shuai under the supervision of Dr. Lincoln Stein, Head of Adaptive Oncology at OICR. DriverPower, as described in a complementary publication in Nature Communications, can help differentiate driver mutations from other ‘passenger’ mutations across whole genomes.

“We now have a remarkably powerful computational tool for future driver discovery,” says Shuai, who is the first author of the Nature Communications publication. “It’s amazing that we can use computational tools and algorithms to find important clues that direct us towards a future where precision medicine is a reality.”

DriverPower identified nearly 100 potential driver mutations which will be evaluated in future studies. As more whole genome sequencing data are collected in the future, DriverPower will continue to be used for driver discovery.

“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 Stein. “With the knowledge we have gained about the origins and evolution of tumours, we can develop new tools and therapies to detect cancer earlier, develop more targeted therapies and treat patients more successfully.”

This work was part of the Pan-cancer Analysis of Whole Genomes Project (known as the Pan-Cancer Project or PCAWG), which was led in part by OICR.

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February 5, 2020

TrackSig: Unlocking the history of cancer

Yulia Rubanova
Yulia Rubanova

Toronto-based machine learning experts map the changes that lead to cancer, revealing opportunities for earlier diagnosis and new approaches to outmaneuver the disease

A tumour is often made up of different cells, some of which have changed – or evolved – over time and gained the ability to grow faster, survive longer and potentially avoid treatment. These cells, which have an ‘evolutionary advantage’, are thought to cause the vast majority of cancer deaths but researchers now have a new tool to tackle tumour evolution: TrackSig.

TrackSig – which was developed by Dr. Quaid Morris and his team at the University of Toronto, the Vector Institute and OICR – is a novel computational method that can map a cancer’s evolutionary history from a single patient sample and in turn help researchers thwart the disease’s next move.

“We combined sequencing with evolutionary theory and mathematical modeling to understand how cancers develop and adapt to resist treatment,” says Yulia Rubanova, PhD Candidate in the Morris Lab and lead author of the study. “This understanding lays the foundation for us to be able to predict – and impede – tumour evolution in future cancer patients.”

This understanding lays the foundation for us to be able to predict – and impede – tumour evolution in future cancer patients
– Yulia Rubanova

TrackSig was published today in Nature Communications alongside nearly two dozen other publications in Nature and its affiliated journals related to the Pan-Cancer Analysis of Whole Genomes Project, also known as the Pan-Cancer Project or PCAWG.

Previous tumour evolution studies focused on identifying the most frequent changes – or mutations – in a patient sample, where the most common mutations represent changes that came earlier in the tumour’s development and less common mutations represent more recent changes. Instead, Morris’ TrackSig charts different types of mutations over time, generating maps of a tumour’s evolutionary history in finer detail and with better accuracy than ever before.

This level of resolution enabled the discovery that many cancer-causing genetic changes occur long before the disease is diagnosed.

“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 Dr. Lincoln Stein, Head of Adaptive Oncology at OICR and member of the Pan-Cancer Project Steering Committee. “This opens up a much larger window of opportunity for earlier detection and treatment than we thought possible.”

The tools and findings from the Pan-Cancer Project are changing the way we think about cancer
Dr. Quaid Morris

With their new detailed maps of tumour evolution, the research group plans to further investigate novel cancer treatment strategies and design new therapies that can better anticipate, prevent and overcome evolution and drug resistance.

“The tools and findings from the Pan-Cancer Project are changing the way we think about cancer,” says Morris. “We’ve uncovered new opportunities to improve diagnosis and treatment, and we’ll continue to strive towards getting the best treatment to patients at the right time.”

TrackSig is freely available for the research community to use at https://github.com/morrislab/TrackSig.

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February 5, 2020

Unraveling the story behind the cancers we can’t explain

Dr. Philip Awadalla
Dr. Philip Awadalla

The Pan-Cancer Analysis of Whole Genomes Project has shown that despite cancer’s complexities, researchers are close to cataloguing all of the biological mechanisms that lead to the disease.

Today, Nature released a special collection of 23 publications related to the analysis, one of which presents the most comprehensive catalogue of RNA alterations in cancer to date.

We sat down with Dr. Philip Awadalla, OICR investigator and National Scientific Director of the Canadian Partnership for Tomorrow Project, and Dr. Fabien Lamaze, Postdoctoral Fellow in the Awadalla Lab, to discuss.

What can RNA show us about cancer?

PA: Cancer is thought to be a disease of the genome, where changes – or mutations – in an individual’s DNA accumulate and eventually lead to the development of the disease. Often, we can identify the mutations that drive this development, figure out the related mechanisms and design new therapies with that information, but sometimes no such ‘driver mutation’ exists.

We believe that RNA can help us unravel the story behind these cancers that we can’t yet explain.

What did the study find?

Dr. Fabien Lamaze
Dr. Fabien Lamaze

FL: In this study, we took a deep dive into the transcriptome – the RNA – of nearly two thousand tumour samples donated by patients from around the world, representing 27 different types of tumours. The group found more than 1.5 million different RNA alterations and related mechanisms in these samples, exposing the true complexity of the disease.

Interestingly, the study found key RNA alterations in patient samples with no DNA driver mutation. This suggests that some of the cellular changes that lead to cancer may manifest in RNA rather than DNA mutations.

What does this mean for the future of cancer research?

PA: We see that cancer is complex and we need even more data to fully understand it, but we’ve also shown that we can make this happen by working together.

FL: The Pan-Cancer Analysis of Whole Genomes Project was the product of an enormous international study that was only made possible by the dedication and true collaboration between thousands of researchers from around the world. For this study, in particular, I’d like to recognize the scientific leadership of Dr. Angela Brooks and collaborators from the University of California, Santa Cruz.

PA: As more patient samples are collected and sequenced, we look forward to using the software tools and infrastructure from the Pan-Cancer Project to gain further insights into cancer biology.

How can this help cancer patients?

FL: Understanding the changes that lead to cancer can help us design better tests and new treatments for future cancer patients. This study, for example, discovered six interesting gene fusions involved with cancer, where two genes come together, join in an abnormal way and wreak havoc. In the future, we could potentially develop new drugs that target the downstream products of these fusions and stop them from causing further damage in the cell.

PA: With the knowledge we’ve gained in this study, we look forward to furthering diagnostic and therapeutic research and development so we can ultimately treat patients more successfully. Work is already underway to make this happen.

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February 5, 2020

Discovering cancer’s vulnerabilities: The whole may be greater than the sum of its parts

OICR and Pan-Cancer Project researchers map key cancer pathways, signposting new directions for its diagnosis and treatment

What works in a lab experiment doesn’t always work in the complex human body. But as technology advances, researchers are gaining the ability to study different features of a cancer cell and the interactions, mechanisms and pathways between them. As more data become available, however, it is becoming increasingly difficult to find the most important molecular pathways that, when blocked, can stop the progression of the disease.

Dr. Jüri Reimand’s lab specializes in this area.

“Researchers often collect molecular data on one aspect of a cancer cell at a time, like its DNA, RNA or proteins,” says Reimand, who is an OICR Investigator. “If we can weave these complex molecular datasets together into a bigger picture, we can gain a more thorough understanding of cancer and potentially find new ways to tackle the driving mechanisms behind the disease.”

Decoding the donors’ data

Thanks to more than 2,500 patient donors from around the world, the Pan-Cancer Project presented one of the largest cancer datasets to date. The Project made hundreds of terabytes of data available to the global cancer research community in a coordinated effort to advance our understanding of the disease.

To help interpret these data, the Reimand Lab developed ActivePathways – a statistical method that can discover significant pathways across multiple molecular omics datasets. These methods, published today in Nature Communications, allow researchers to characterize the cell at a systems-level, decipher how the components interact and tease out the most important pathways.

“We designed a simplified approach to tackle one of the largest cancer genomics datasets to date,” says Reimand. “With these methods we can now chart important interactions that we wouldn’t have recognized by looking at one component or dataset alone.”

The power of the ensemble

The Reimand Lab teamed up with researchers in Belgium, Norway, Spain, Switzerland and across the U.S. who were also interested in analyzing the important pathways within the Pan-Cancer Project dataset. They combined their methods and expertise and identified nearly 200 important driver pathways across 38 different cancer types.

Their findings showed that cancer cells often have related or coordinated mutations in the coding regions and the non-coding regions of the genome.

Now, we have better methods and stronger evidence to move forward as we investigate how to block these pathways, and further, block the progression of the disease.
– Dr. Jüri Reimand

“Together, we came to a consensus list of frequently mutated molecular pathways, processes and target genes,” says Reimand. “Now, we have better methods and stronger evidence to move forward as we investigate how to block these pathways, and further, block the progression of the disease.”

All tools, methods and data related to the collaboration are freely available for the research community to use for future research.

“We’re proud of this progress,” says Reimand. “We look forward to the future research that will build on these findings towards better cancer diagnostic tests and treatment options.”

Related links

January 20, 2020

New tumour-driving mutations discovered in the under-explored regions of the cancer genome

Dr. Jüri Reimand, OICR Investigator and lead author of the study.

OICR researchers identify novel causes of cancer progression in the non-coding genome, opening new lines of investigation for several cancer types

Toronto – (January 20, 2020) In an unprecedented pan-cancer analysis of whole genomes, researchers at the Ontario Institute for Cancer Research (OICR) have discovered new regions of non-coding DNA that, when altered, may lead to cancer growth and progression.

The study, recently published in Molecular Cell, reveals novel mechanisms of disease progression that could lead to new avenues of research and ultimately to better diagnostic tests and precision therapies.

Although previous studies have focused on the two per cent of the genome that codes for proteins, known as genes, this study analyzed mutation patterns within the vast non-coding regions of human DNA that control how and when genes are activated.

We found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumours.

“Cancer-driver mutations are relatively rare in these large non-coding regions that often lie far from genes, presenting major challenges for systematic data analysis,” says Dr. Jüri Reimand, investigator at OICR and lead author of the study. “Powered by novel statistical tools and whole genome sequencing data from more than 1,800 patients, we found evidence of new molecular mechanisms that may cause cancer and give rise to more-aggressive tumours.”

The research group analyzed more than 100,000 sections of each patient’s genome, focusing on the often-overlooked non-coding regions that interact with genes through the three-dimensional genome. One of the 30 key regions discovered was predicted to have a significant role in regulating a known anti-tumour gene in cancer cells, despite being more than 250,000 base pairs away from the gene in the genome. The group performed CRISPR-Cas9 genome editing and functional experiments in human cell lines to explore the cancer-driving properties of this non-coding region.

“We characterized several non-coding regions potentially involved in oncogenesis, but we’ve just scratched the surface,” says Reimand. “With our algorithms and the rapidly growing datasets of patient cancer genomes and epigenetic profiles, we look forward to enabling future discoveries that could lead to new ways to predict how a patient’s cancer will progress and ultimately new ways to target a patient’s disease or diagnose it more precisely.”

Reimand’s research group developed the statistical methods behind this study and made them freely available for the research community to use. These methods have been rigorously tested against other algorithms from around the world.

We’ve shown that our method, called ActiveDriverWGS, can excavate these regions and pinpoint specific areas that are important to cancer growth.

“Looking into the non-coding genome is really important because these vast sections regulate our genes and can switch them on and off. Mutations in these regions can cause these regulatory switches to act abnormally and potentially cause – or advance – cancer,” says Helen Zhu, student at OICR and co-first author of the study. “We’ve shown that our method, called ActiveDriverWGS, can excavate these regions and pinpoint specific areas that are important to cancer growth.”

“Although these candidate driver mutations are rare, we now have the first experimental evidence that one of the mutated regions regulates cancer genes and pathways in human cell lines,” says Dr. Liis Uusküla-Reimand, Research Associate at The Hospital for Sick Children (SickKids) and co-first author of the study. “As the research community collects more data, we plan to look deeper into these regions to understand how the mutations alter gene regulation and chromatin architecture in specific cancer types to enable the development of new precision therapies to patients with these diseases.”

This study was supported by OICR through funding provided by the Government of Ontario, and by the Canadian Institutes of Health Research (CIHR), the Cancer Research Society (CRS), the Estonian Research Council, and the Natural Sciences and Engineering Research Council of Canada (NSERC).

Whole genome sequencing data used in this study was made available by the International Cancer Genome Consortium’s Pan-cancer Analysis of Whole Genomes Project (ICGC PCAWG), also known as the PCAWG Project or the Pan-Cancer Project.

January 13, 2020

Unique Toronto-based clinical trial reveals new subtypes of advanced pancreatic cancer

Drs. Faiyaz Notta and Steven Gallinger, Co-Leaders of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx).

Researchers identify five subtypes of pancreatic cancer, uncovering new opportunities for targeted treatment of the aggressive disease

Toronto – (January 13, 2020) Researchers at the Ontario Institute for Cancer Research (OICR) and the University Health Network (UHN) have discovered detailed new information about the subtypes of pancreatic cancer. A better understanding of the disease groups may lead to new treatment options and improved clinical outcomes for this lethal disease.

The study, published today in Nature Genetics, represents the most comprehensive analysis of the molecular subtypes of pancreatic cancer to date. Through detailed genomic and transcriptomic analyses, the research group identified five distinct subtypes of the disease (Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid) with unique molecular properties that could be targeted with novel chemotherapies, biologics and immunotherapies.

“Therapy development for pancreatic cancer has been hindered by an incomplete knowledge of the molecular subtypes of this deadly disease,” says lead author Dr. Faiyaz Notta, Co-Leader of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx) and Scientist at UHN’s Princess Margaret Cancer Centre. “By rigorously analyzing advanced pancreatic cancers – which is the stage of disease that most patients have when they’re diagnosed – we were able to create a framework. This will help us develop better predictive models of disease progression that can assist in personalizing treatment decisions and lead to new targeted therapies.”

The study is based on data from more than 300 patients with both early stage and advanced pancreatic cancer who participated in COMPASS, a first-of-its-kind clinical trial that is breaking new ground in discovery science and personalized pancreatic cancer treatment. COMPASS is enabled by advanced pathology laboratory techniques at UHN and OICR, and next generation sequencing at OICR.

“Most pancreatic cancer research is focused solely on early stage – or resectable – tumours, but in reality, pancreatic cancer is often found in patients after it has advanced and spread to other organs,” says Notta. “COMPASS allowed us to look into these advanced cancers while treating these patients, develop a better understanding of the biology behind metastatic pancreatic cancer, and shed light on the mechanisms driving disease progression.”

Interestingly, the Basal-like-A subtype, which had been difficult to observe before this study, was linked with a specific genetic abnormality. Most of the Basal-like-A tumours harboured several copies of a mutated KRAS gene, also known as a genetic amplification of mutant KRAS. The research group hypothesizes that some of the subtypes arise from specific genetic changes that occur as pancreatic cancer develops.

“This research opens new doors for therapeutic development,” says Dr. Steven Gallinger, Co-Leader of OICR’s PanCuRx, Surgical Oncologist at UHN and Senior Investigator, Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital. “We look forward to capitalizing on the promise of these discoveries, building on our understanding of pancreatic cancer subtypes, and bringing new treatments to patients with the disease.”

This research was supported by OICR through funding provided by the Government of Ontario, and by the Wallace McCain Centre for Pancreatic Cancer by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, the Pancreatic Cancer Canada Foundation, the Canadian Friends of the Hebrew University and the Cancer Research Society (no. 23383).

January 10, 2020

New open-source software judges accuracy of algorithms that predict tumour evolution

Adriana Salcedo
Adriana Salcedo

OICR-led international research group develops new open-source software to determine the accuracy of computational methods that can map the genetic history of tumour cells.

A cancer patient’s tumour is often made up of many cells with different genetic traits that can evolve over time. Interest in tumour evolution has grown over the last decade, giving rise to several new computational tools and algorithms that can characterize genetic diversity within a tumour, and infer patterns in how tumours evolve. However, to date there has been no standard way to compare these tools and determine which are most accurate at deciphering these data.

The genetic differences between tumour cells can tell us a lot about a patient’s disease and how it evolves over time – Adriana Salcedo

In a study recently published in Nature Biotechnology, an OICR-led international research group released new open-source software that can be used to judge the accuracy of these novel algorithms.

Continue reading – New open-source software judges accuracy of algorithms that predict tumour evolution

December 19, 2019

New immune-boosting approach could halt the spread of cancer cells to nearby organs

Dr. Victoria Hoskin, Postdoctoral Fellow at Queen’s Cancer Research Institute.

Dr. Victoria Hoskin, OMPRN grantee, wins best poster presentation at the 2019 Terry Fox Research Institute Ontario Node Research Symposium for her novel approach to preventing cancer metastasis

The vast majority of cancer-related deaths are caused by cancers that have spread – or metastasized – to other organs. Breast cancer cells, for example, often spread to nearby lymph nodes where they can settle, grow and spread to more distant organ sites, evading surgery and chemotherapy treatment. Dr. Victoria Hoskin has set out to stop these migrating cancer cells in their tracks.

Earlier this year, Hoskin and an interdisciplinary team of researchers at Queen’s Cancer Research Institute (QCRI), found that a specific protein, ezrin, which plays a key function in cancer metastasis, may also have an important immune-modulating role. They went on to find that when ezrin is blocked, the immune system’s T-cells can better recognize, engage and kill the migrating cancer cells in surrounding lymph nodes. As she describes in her recent Oncotarget editorial, these findings may represent a new method to not only prevent cancer metastasis, but to also engage the immune system.

“When we blocked ezrin, we saw that the cancer cells couldn’t migrate and invade into other tissues,” says Hoskin, who is a Postdoctoral Fellow at QCRI. “We’re excited by these findings because they point to a new way to reduce the spread of cancer cells and to potentially boost the immune response against these cancer cells.”

Throughout the course of her research, which was supported in part by the Ontario Molecular Pathology Research Network (OMPRN), Hoskin helped develop a novel experimental animal model that allowed her and her team to track and monitor cancer and immune cells in vivo. The model, she describes, was the critical tool behind her discovery, allowing her to look deeper into the behavior of cancer cells and T-cells within specific organs.

Last week, Hoskin presented her research at the 2019 Terry Fox Research Institute Ontario Node Research Symposium. Among more than 120 other presenters, she won one of three poster presentation awards. Other presentation award recipients included:

  • Parasvi Patel, PhD Candidate, University of Toronto and Princess Margaret Cancer Centre
  • Noor Shakfa, MSc Candidate, Queen’s University and Queen’s Cancer Research Institute

Hoskin and her collaborators plan to further investigate how T-cells interact with cancer cells in the absence of ezrin.

“What we’ve found is not only scientifically interesting, it could be clinically significant,” says Hoskin. “Metastasis is a serious challenge and our research efforts are dedicated to finding a new solution.”

Learn more about OMPRN

Read more about the 2019 TFRI Ontario Node Research Symposium.

December 6, 2019

Pin-pointing prostate cancer: Bringing MRI-guided biopsies to men across Ontario

Dr. Laurence Klotz of the Sunnybrook Research Institute
Dr. Laurence Klotz, urologic surgeon and researcher at Sunnybrook Health Sciences Centre.

OICR-funded clinical trial shows value in advanced biopsy techniques for men with low-risk prostate cancer

Many of the 23,000 men across Canada who will be diagnosed with prostate cancer this year won’t need aggressive treatment. Instead, men with low-risk or slow-growing cancers may be offered ‘active surveillance’, where their healthcare team monitors their cancer closely with regular tests, scans and biopsies. Dr. Laurence Klotz, a world leader in active surveillance, is working to improve how surgeons in Ontario and across Canada perform these important prostate biopsies.

Klotz, who is a leading urologic surgeon and researcher at Sunnybrook Health Sciences Centre, teamed up with collaborators in London, Hamilton, Kitchener and Toronto to bring the latest MRI-guided prostate biopsy techniques to patients across the province. With OICR’s support, they evaluated the use of MRI-targeted biopsies, where a surgeon uses MRI images to help guide biopsy needles, relative to traditional biopsies, and found that the use of MRI results in 50 per cent fewer failures of surveillance. The findings from their two-year study were recently published in European Urology.

“As shown in other countries like the U.K. and Australia, using MRI before biopsies can reduce the diagnosis of insignificant cancers, selectively find aggressive cancers and reduce the number of false negatives,” says Klotz. “Our study showed that using MRI allows us to better pinpoint prostate cancers as they progress.”

Learnings from this study have helped inform the design of a new trial, called PRECISE, that is evaluating whether MRI can replace biopsies and spare some men from the associated side effects. Results from PRECISE will be submitted for publication in the next few months.

“We’ve laid the groundwork for better prostate cancer diagnosis,” says Klotz. “This means we’re one step closer to ensuring each man receives the most appropriate treatment for his individual cancer.”

Read more about PRECISE.

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