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Publications of the Week

Improved Structural Variant Interpretation for Hereditary Cancer Susceptibility Using Long-Read Sequencing

By July 13, 2020No Comments

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This week we profile a recent publication in Genetics in Medicine from the laboratories of Dr. Steven Jones (pictured, left)
and Dr. Kasmintan Schrader (right) at Canada’s Michael Smith Genome Sciences Centre and BC Cancer.

Can you provide a brief overview of your lab’s current research focus?

Dr. Steven Jones’ lab at Canada’s Michael Smith Genome Sciences Centre uses bioinformatics to investigate the landscape of mutations present in cancer genomes and the early genomic events that give rise to and promote the progression of cancer. To achieve these goals, his laboratory analyzes next generation sequencing data and develops novel computational approaches and methodologies. A significant aim of Dr. Jones’ research program is to find innovative ways to exploit specific genomic profiles within an individual cancer for therapeutic purposes. For example, his team has identified several epigenetic modifications that may potentially be targeted to reverse the effects of cancer initiating mutations. His lab is also using computational approaches, such as molecular docking and molecular dynamics, to identify and refine compounds that can modify the cancer epigenome.

Technological advances in precision oncology have primary focused on cancer treatment and detection of recurrent disease. Dr. Kasmintan Schrader’s lab at BC Cancer leverages precision oncology platforms to improve hereditary cancer detection, better differentiate hereditary versus non-hereditary forms of cancer, detect cancer earlier, and uncover germline variation that may not only confer increased cancer susceptibility, but may provide other significant information to the cancer patient, family and their care providers.

What is the significance of the findings in this publication?

Whole genome sequencing has revolutionized cancer treatment planning, enabling the rapid detection of DNA mutations not routinely screened for in the clinic. Until recently, however, scientists were limited in their ability to detect large structural genetic variants using short-read sequencing technology. But with the recent release of long-read sequencing instruments, cancer researchers have been eager to see what such technology could mean for precision oncology.

In this study, researchers employed the Oxford Nanopore PromethION (a long-read sequencer recently added to the armament of instruments at the GSC’s technology platform), to re-sequence and analyze the genomes of cancer patients enrolled in BC Cancer’s Personalized OncoGenomics (POG) program, which were previously sequenced using only short-read technology.

The researchers focused on germline variants—those that are inherited and shared among family members—which may influence cancer susceptibility, formation, progression and treatment outcomes. While germline variants in cancer predisposition genes underlie five to 10 per cent of all cancers, many patients who appear to have a hereditary predisposition to cancer cannot be provided with a genetic explanation using standard clinical assays. The findings of this study suggest that, for these patients, long-read sequencing may be advantageous to confirm the presence or absence of germline structural variants that may have implications for their disease.

What are the next steps for this research?

Integration of long-read sequencing into a program like POG requires technology development and optimization. As part of this study, the group developed processes for aligning long-read sequencing data and for detecting variants. Moving forward, further development is needed to allow for the detection of variants without prior knowledge.

This work was funded by:

We gratefully acknowledge Genome Canada, Genome BC, the Canada Foundation for Innovation, the BC Knowledge Development Fund, the BC Cancer Foundation, the University of British Columbia Clinician Investigator Program, the Canadian Institutes for Health Research and the Michael Smith Foundation for Health Research

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