New study highlights long-read sequencing applications in precision oncology

Precision oncology relies on understanding each individual tumour’s molecular makeup. Long-read sequencing provides new ways to do that.

Sequencing technologies have revolutionized our ability to study the molecular features of cells, such as their DNA and RNA. This has been particularly impactful in cancer – a collection of diseases driven by molecular alterations – where the ability to sequence both tumour and normal cells has helped greatly expand our understanding of how cancers arise and behave and how they can be treated more effectively. 

In the past two decades, sequencing technologies have advanced rapidly, leading to increased scalability, reduced costs, and new profiling capabilities. One important innovation has been the introduction of long-read sequencing methods. The sequencing methods most commonly used today involve breaking DNA into small pieces (on the order of hundreds of bases, or “letters” of the DNA code) before reassembling these pieces back together using computational approaches – this is called “short-read sequencing”. 

Long-read sequencing methods take an entirely different approach to “reading” DNA, and can produce so-called “sequencing reads” that are tens of thousands of bases long or more. With their higher informational content, these longer reads can more easily be “mapped” back to the genome, providing more accurate information about each read’s genomic context. This is especially powerful in the study of cancer, where complex genetic rearrangements and other alterations are common and can be difficult or impossible to decode using short-read sequencing. 

Despite its promise, long-read sequencing remains challenging to implement and, at least in the context of cancer, has mostly been deployed in smaller studies. In a new study published this week in Cell Genomics, a team led by Dr. Steven Jones (BC Cancer) present an unparalleled analysis of 189 patient tumour samples profiled with long-read sequencing and demonstrate how this technology can be applied in the context of precision oncology. 

The study was performed as part of the Personalized Oncogenomics (POG) program at BC Cancer and Canada’s Michael Smith Genome Sciences Centre, and was partially funded by the Marathon of Hope Cancer Centres Network. The dataset analyzed in the study also includes accompanying short-read sequencing data and will be contributed to the Network’s Gold Cohort resource.  

By generating both short- and long-read sequencing data from the same samples, the authors were able to compare the two technologies and begin to understand what kind of questions are best answered by each method or by a combination of the two. Dr. Erin Pleasance, co-first author on the study, explains that based on the findings from this study, the POG program now aims to apply long-read sequencing to all participating patients where appropriate samples are available. 

The study underscores that long-read sequencing may provide a unique opportunity to reveal clinically relevant information in, for example, patients whose tumours contain complex genetic alterations that cannot be decoded with short-read sequencing data, patients whose tumours have defects in DNA repair activity (i.e. are HRD+) but no known mutations that cause this phenotype, or patients with a family history of cancer where no clear causal mutation can be identified. 

Importantly, the authors are also making their data – including not only sequencing data but also the computational tools and algorithms used to analyze it – available to the research community to help stimulate further research in this field. “Until now, the absence of a sizeable cohort of patient-derived cancer cases profiled with long-read sequencing has delayed the development of analytical tools that are specifically suited to cancer,” says co-first author Dr. Kieran O’Neill. “This dataset will be an important resource to support precision oncology research based on long-read sequencing.” 

“While short-read sequencing continues to be a powerful tool for precision oncology, long-read sequencing can contribute valuable additional insights into tumour biology and precision oncology,” highlights Dr. Jones. “With the support of MOHCCN, Canadian researchers can incorporate new technologies to push the boundaries of cancer research and improve the lives of cancer patients in Canada and around the world.” 

​​Sequencing of patient samples for this study was partially funded by the Marathon of Hope Cancer Centres Network. These samples are now part of the MOHCCN Gold Cohort, which means that in the future, other researchers may use these data to further their precision medicine studies.​ 

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