Drs. Kasmintan Schrader (left) and Stephen Yip (right), are recipients of the UBC Faculty of Medicine 2021/2022 Precision Health Catalyst Grant award for their project titled “Parent-of-Origin-Aware Hereditary Cancer Diagnostic and Cascade Genetic Testing”.
Read a summary of the project here.
“The future of precision health will be driven by constantly evolving technological advancement and the development of novel analytical methodology.”
Can you tell us about the precision health research work you’re collaborating on?
KS: Our team, including Steven Jones, and Peter Lansdorp and their very talented trainees, has figured out a way to understand a variant’s parent-of-origin using only the blood sample from the child. This is a novel and landmark technology for the field of genetics that allows us to understand the exact genetic contributions from the mother and father, without the need for samples from any family members or external data. It has numerous potential research and clinical applications that we are excited to be exploring.
Can you explain a bit more about this novel technology?
SY: We utilized cutting edge STRAND-Seq and epigenome-wide profiling on the Oxford Nanopore Technology- Long Read Sequencing (ONT-LRS) platform to infer the parent-of-origin of disease- causing pathogenic variant. This allows us to save both time and money in the context of hereditary cancer workup for sequencing and additional screening of family members. This will ultimately allow us to efficiently identify patients and family members at risk for cancer development and will also inform on novel genomic and epigenomic causes of diseases.
KS: This method also seems to work across different population groups and may not be subject to the same difficulties from underrepresentation of different populations that typically hinder clinical and research genetics.
What results have you seen so far?
KS: With funding from the UBC Faculty of Medicine’s Precision Health Catalyst Grant we were able to rapidly begin validation of the technology in a critical use case that involves the SDHD gene. When a pathogenic variant in SDHD is inherited from the father there is an up to 60% chance of developing rare tumors, such as paragangliomas and pheochromocytomas, over a person’s lifetime. If the pathogenic variant is inherited from the mother, the risk is minimal. This has significant clinical implications for carriers of SDHD pathogenic variants for whom intensive screening and life-long surveillance is recommended when the variant is inherited from the father or when parental segregation is unknown. Of note, screening and surveillance is not needed when the pathogenic variant is known to be inherited from the mother. To date, we have seen 100% concordance between the predicted and known variant parent-of-origin using real-world blood samples from 18 participants. These results are extremely exciting as they give us confidence that this technology could significantly impact clinical care of these patients in the future.
SY: Proof of principle, technical and bioinformatic validation of the work has since been published (PMID 36777186). Also, we are performing ongoing assessment of this technology on cases with known genomic alterations as part of a process that will lead to its eventual clinical adoption in BC. Lastly, the Precision Health Catalyst Grant allowed the team to extend assessment of this technology and also generate invaluable supportive data which was part of our successful applications for both Genome Canada GAPP grant and CIHR Project grant competitions.
From your perspective, what do you think is exciting about the future direction of precision health?
SY: “Omic”- driven data will impact medicine and is already dictating how we manage cancer patients. In oncology, genomic and epigenomic data from germ line (what gets “passed on” to the next generation) and somatic tissue (what is in the cancer tissue) are essential for care. Soon, integration of the transcriptome, proteome, and the tissue- associated microbiome will allow for precision profiling of cancer to uncover therapeutic targets, minimize treatment side-effects, and to effect proper disease prevention. This paradigm is broadly applicable to all aspects of medicine. The ONT-LRS technology highlighted gives us unique insight into the transmission pattern of cancer-causing genes in the context of hereditary cancer investigation. In addition, the same technology can be deployed for the rapid identification of genomic and epigenomic alterations at the somatic level. The future of precision health will be driven by constantly evolving technological advancement and the development of novel analytical methodology. More importantly, the integration of health economic analysis and impact on equity will play an increasingly larger role.
KS: Parent-of-origin-aware genomic analysis is just one example of how technology is continually advancing and making possible things we never thought would be. With continued close collaborations between researchers, clinicians, and the encouragement of multidisciplinary interactions, it is exciting to consider how quickly some of our toughest clinical issues may be solved by team efforts and cross-pollination of ideas. Local support of precision health initiatives like the Faculty of Medicine’s Precision Health Catalyst Grant enabled us to accelerate our validation, generate preliminary data and gain national funding support from Genome Canada and CIHR. As precision health becomes more mainstream, we are excited to explore the many applications of parent-of-origin-aware genomic analysis and meet the growing need to accurately and equitably interpret patient genetic information.
About Dr. Kasmintan Schrader
Dr. Kasmintan Schrader is a Clinician-Scientist, Medical Geneticist who received her PhD in Pathology and Laboratory Medicine at the University of British Columbia. She trained in cancer susceptibility gene discovery at Memorial Sloan Kettering in New York and returned to BC in 2014 to build the Familial Pancreatic Cancer Program. In 2016, she became Co-Medical Director of BC Cancer’s Hereditary Cancer Program and in 2021 was awarded a Tier 2 Canada Research Chair in Clinical Cancer Genetics and Genomics. Dr. Schrader investigates the utility of germline variation in overall cancer care and prevention; to harness precision oncology for the benefit of patients and families.
About Dr. Stephen Yip
Dr. Stephen Yip completed his combined M.D-Ph.D. training followed by 4 years of neurosurgical training at UBC. He switched to neuropathology and obtained his FRCPC certification in 2007. He completed fellowship training in molecular neuro-oncology at the Massachusetts General Hospital under the mentorship of Dr. David Louis as a Royal College Clinician Investigator Program fellow and molecular genetic pathology at MGH/Harvard Medical School under the supervision of Dr. John Iafrate. Stephen is on staff at Vancouver General Hospital and is the medical director of clinical genomics at BC Cancer. He is a recipient of the 2023 Michael Smith Health Research BC Health Professional Investigator award.