October 7, 2019

Inherited DNA provides blueprint for new advancements in prostate cancer

Kathleen Houlahan, first author of the study and a PhD candidate at OICR.

International study, led by researchers at OICR, takes a deep dive into how prostate cancer is inherited and points to new opportunities for improved screening, monitoring, treatment and prevention

Prostate cancer is one of the most common cancers in men, but remains one of the most difficult to prevent and a challenge to treat. Some DNA mutations that lead to prostate cancer are inherited yet some collect over a lifetime. Understanding how these mutations interact and contribute to the disease could help patients and their doctors better manage the disease.

In a study, published today in Nature Medicine, Kathleen Houlahan et al. take a deep dive into the inherited factors driving prostate cancer and how these factors affect the course of the disease at a cellular level.

“Prostate cancer is thought to be, in part, an inherited disease,” says Houlahan, first author of the study and a PhD candidate at OICR. “The DNA that a man is born with has an effect on whether he will develop prostate cancer and how aggressive the cancer will be. We set out to uncover how this happens.”

The study investigated the connection between inherited mutations – also known as germline mutations – and a range of important DNA-regulating processes, like DNA methylation.

The associations found in the study, Houlahan says, are a resource that can help bridge our gap in understanding between germline mutations and the mutations that men acquire over their lifetime that eventually lead to prostate cancer.

“When we understand how inherited mutations work, patients with these mutations can be screened and monitored more effectively to ensure the patient is receiving the most appropriate treatment and avoiding unnecessary side effects,” says Houlahan. “We’ve seen this work for patients with mutations in the BRCA genes, but we still need more personalized options for the many men who are living with prostate cancer.”

Since germline mutations can be inherited and are present in nearly all cells in a man’s body, this research demonstrates the possibility of using non-invasive blood-based tests, rather than invasive tumour biopsies, to monitor prostate cancers.

“We could use these findings to help identify a man’s risk of cancer and catch it earlier,” says Houlahan. “Detecting the disease earlier could significantly improve treatment success.”

Houlahan’s study was enabled by data from the Canadian Prostate Cancer Genome Network (CPC-GENE), which have previously been used to find a DNA signature of aggressive prostate cancers and link how a prostate tumour evolves with the severity of the tumour, amongst other significant advancements. CPC-GENE findings serve as a resource for future research and a scaffold on which diagnostic tests and new therapies can be built. 

This research was supported in part by OICR, Prostate Cancer Canada, the Terry Fox Research Institute, the Canadian Institutes for Health Research, the Canadian Cancer Society, the Movember Foundation and the National Cancer Institute.

March 13, 2019

When it comes to prostate cancer, there may be more than meets the eye

Researchers begin to unravel why some prostate tumours can be seen with magnetic resonance imaging and others go undetected

Determining whether a patient with prostate cancer requires aggressive therapy or active surveillance is a growing challenge for the healthcare system. Blood tests can detect early signs of prostate cancer, but these tests can lead to many unnecessary and painful biopsies for patients whose disease never becomes aggressive.

Multi-parametric magnetic resonance imaging (mpMRI), a type of non-invasive imaging technique, has the potential to help determine which patients require biopsies and which can be spared possible negative side effects, such as bleeding, pain and infection. Some tumours are visible by mpMRI while some are not, yet it’s not well understood if this visibility can predict a tumour’s aggressiveness.

Researchers at OICR have teamed up with clinicians from the University of California, Los Angeles to investigate the molecular properties of MRI-visible and MRI-invisible tumours. In their recent study, published in European Urology, they found that visible tumours have similar features to aggressive tumours and discovered new features that may be contributing to the disease’s aggression. 

“Even if two tumours are similar in size and in similar positions, one still may be MRI-visible and one may be MRI-invisible,” says Kathleen Houlahan, PhD Candidate at OICR and lead author of the study. “We wanted to see if this visibility could help us determine if a cancer is aggressive, so we took the first step towards unraveling the relationship between a patient’s MRI results and the molecular characteristics of their tumour.”

Recent commentary on the study highlights Houlahan’s work as an “initial foray” into the intersection of radiology, pathology and genomics, but recognizes the limited size of her exploratory study. Recent MRI-focused clinical trials will provide larger datasets for further investigation.

 “If we can better understand why some tumours show and some don’t, we could potentially use imaging to predict the course that a patient’s disease will take,” says Houlahan. “Ultimately, we hope that this technique can help reduce unnecessary prostate biopsies and ensure that the men who need treatment get the treatment they need.”

May 18, 2015

Research community comes together to provide new “gold standard” for genomic data analysis

TORONTO, ON (May 18, 2015) – Cancer research leaders at the Ontario Institute for Cancer Research, Oregon Health & Science University, Sage Bionetworks, the distributed DREAM (Dialog for Reverse Engineering Assessment and Methods) community and The University of California Santa Cruz published the first findings of the ICGC-TCGA-DREAM Somatic Mutation Calling (SMC) Challenge (The Challenge: https://www.synapse.org/#!Synapse:syn312572) today in the journal Nature Methods. These results provide an important new benchmark for researchers, helping to define the most accurate methods for identifying somatic mutations in cancer genomes. The results could be the first step in creating a new global standard to determine how well cancer mutations are detected.

The Challenge, which was initiated in November 2013, was an open call to the research community to address the need for accurate methods to identify cancerassociated mutations from whole-genome sequencing data. Although genomic sequencing of tumour genomes is exploding, the mutations identified in a given genome can differ by up to 50 per cent just based on how the data is analyzed.

Research teams were asked to analyze three in silico (computer simulated) tumour samples and publicly share their methods. The 248 separate analyses were contributed by teams around the world and then analyzed and compared by Challenge organizers. When combined, the analyses provide a new ensemble algorithm that outperforms any single algorithm used in genomic data analysis to date.

The authors of the paper also report a computational method, BAMSurgeon (developed by co-lead author Adam Ewing, a postdoctoral fellow in the lab of Dr. David Haussler at UC Santa Cruz), capable of producing an accurate simulation of a tumour genome. In contrast to tumour genomes from real tissue samples, the Challenge organizers had complete knowledge of all mutations within the simulated tumour genomes, allowing comprehensive assessment of the mistakes made by all submitted methods, as well as their accuracy in identifying the known mutations.

The submitted methods displayed dramatic differences in accuracy, with many achieving less than 80 per cent accuracy and some methods achieving above 90 per cent. Perhaps more surprisingly, 25 per cent of teams were able to improve their performance by at least 20 per cent just by optimizing the parameters on their existing algorithms. This suggests that differences in how existing approaches are applied are critically important – perhaps more so than the choice of the method itself.

The group also demonstrated that false positives (mutations that were predicted but didn’t actually exist) were not randomly distributed in the genome but instead they were in very specific locations, and, importantly, the errors actually closely resemble mutation patterns previously believed to represent real biological signals.

“Overall these findings demonstrated that the best way to analyze a human genome is to use a pool of multiple algorithms,” said co-lead author Kathleen Houlahan, a Junior Bioinformatician at the Ontario Institute for Cancer Research working with the Challenge lead, Dr. Paul Boutros. “There is a lot of value to be gained in working together. People around the world are already using the tools we’ve created. These are just the first findings from the Challenge, so there are many more discoveries to share with the research community as we work through the data and analyze the results.”

“Science is now a team sport. As a research community we’re all on the same team against a common opponent,” said Dr. Adam Margolin, Director of Computational Biology at Oregon Health & Science University and co-organizer of the challenge. “The only way we’ll win is to tackle the biggest, most challenging problems as a global community, and rapidly identify and build on the best innovations that arise from anywhere. All of the top innovators participated in this Challenge, and by working together for a year, I believe we’ve advanced our state of knowledge far beyond the sum of our isolated efforts.”

“Paul and the whole team have done something truly exceptional with this Challenge. By leveraging the SMC Challenge to establish a living community benchmark, the Challenge organizers have made it run more like an “infinite game” where the goal is no longer one of winning the Challenge but instead of constantly addressing an everchanging horizon,” said Dr. Stephen Friend, President of Sage Bionetworks. “And given the complex heterogeneity of cancer genomes and the rapid rate with which next generation sequencing technologies keep changing and evolving, this seems like an ideal approach to accelerate progress for the entire field.”

“We owe it to cancer patients to interpret tumour DNA information as accurately as we can. This study represents yet another great example of harnessing the power of the open, blinded competition to take a huge step forward in fulfilling that vision,” said Josh Stuart, professor of biomolecular engineering at UC Santa Cruz and a main representative of The Cancer Genome Atlas project among the authors. “We still have important work ahead of us, but accurate mutation calls will give a solid foundation to build from.”