Interview: Parent-of-origin genome analysis presents the potential to improve future genetic testing

Kasmintan Schrader is a clinician-scientist and medical geneticist working in the Hereditary Cancer Program at BC Cancer where she investigates the utility of germline variation in overall cancer care and prevention to harness precision oncology for the benefit of patients and families. We caught up with Kasmintan to discuss her research, how she became interested in clinical genetics, and the impact nanopore sequencing is having on understanding the link between germline variation and cancer susceptibility.

You can hear more about Kasmintan’s work in her recent webinar  ‘Parent-of-origin genome analysis presents the potential to improve future genetic testing’.

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What are your current research interests?

In general, my research focuses around improving the diagnosis and management of hereditary cancer. I am very interested in exploring both the potential clinical utility of parent-of-origin-aware genomic analysis and how it may be used to further our understanding of inherited forms of disease.

What first ignited your interest in clinical genetics and what lead you to focus on oncology?

I was always drawn to clinical genetics because of the inherently fascinating nature of heredity, but also because of the important ethical, psychosocial, as well as societal issues and considerations continually raised by advances in the field. Through my eyes, genetics appeared to be moving fastest in oncology and so I’ve always been keen to be in that space. When I had the chance to train with Dr. David Huntsman, who played a critical role in defining the management of an inherited susceptibility to diffuse gastric cancer due to mutations in the CDH1 gene, I was struck by how rapidly research findings, such as a research-identified pathogenic variant in CDH1, could be clinically translated to ultimately save lives. By giving at-risk family members the opportunity to undertake carrier testing for the familial CDH1 pathogenic variant and subsequent prophylactic gastrectomy, if found to be positive, it essentially removes their very high lifetime risk for gastric cancer. I was hooked.

How is nanopore sequencing helping to better understand how germline variation effects cancer susceptibility? How has it benefited your work?

This is an exciting question that we have just scratched the surface on. I think these next few years will be intriguing as we apply nanopore sequencing to more and more hereditary cancer cases. It is very clear nanopore sequencing is excellent at resolving structural variation, but also has a powerful and impactful ability to resolve differential methylation, which is demonstrated by its use in parent-of-origin-aware genomic analysis. These capabilities have greatly benefited our research through accurate characterisation of structural variants of uncertain significance, to the development of parent-of-origin-aware genomic analysis.

What impact could the ability to simply and accurately assign variants to the parent of origin have for precision medicine?

The ability to assign parent-of-origin to any autosomal variant stands to have a tremendous impact on every day clinical genetics activities, such as variant curation and interpretation, risk management, cascade genetic testing, and informing recurrence risk, to name a few. One of the most striking areas of impact could be for variants with parent-of-origin effects where interpretation of disease risk and subsequent management relies on knowing parental segregation. This disadvantages patients who are adopted, or whose parents are deceased, or otherwise unavailable to undertake genetic testing. So understanding variant parent-of-origin adds a new dimension to genetic and genomic analysis that has not previously been encountered without additional family or other ancestral data. Of importance, it appears to work well across different ethnicities, which is meaningful considering the higher rates of variants of uncertain significance in underrepresented populations in public variant databases.

What have been the main challenges in your work and how have you approached them?

During our initial validation of parent-of-origin-aware genomic analysis, we encountered lower sequence coverage, suspected to be related to the DNA extraction method used for the real-world samples. On the bright side, we learned that we were still able to accurately predict parent-of-origin with these lower coverage samples. Although this natural experiment was useful, we have since optimised DNA extraction methods.

Another potential challenge has been related to the novelty of the parent-of-origin-aware genomic analysis method. With the adoption of any new technology comes the need to educate the community and examine the ethical considerations. Although the ethical issues raised by predicting parent-of-origin with such high accuracy are not new to clinical genetics (e.g. considering the genetic testing of an identical twin, or revealing obligate carrier status through carrier testing), the scale at which they could occur could be unprecedented, and therefore require careful consideration. To consider the full scope of ethical considerations we recruited our genetics trained clinical ethicist to join our study team.

What’s next for your research?

We are extremely grateful to have received grant funding from Genome Canada and the Canadian Institutes for Health Research to validate parent-of-origin-aware genomic analysis across various hereditary cancer syndromes and explore its potential clinical utility. I am also looking forward to starting to pose some of the many other questions related to cancer and beyond that this novel method allows us to now consider.