Orthogonal pangenome sequencing to unveil genetic cancer susceptibility diagnostic odysseys: a Return of Results Working Group new technology assessment study

Using long-read sequencing to reveal unknown hereditary links to cancer

The first thing most doctors think about when one of their patients is diagnosed with cancer at a young age or has a strong family history of the disease is that they carry a hereditary predisposition to cancer. Confirming this suspicion has big implications for both the patient and their family members, as targeted therapies and screening protocols can be activated by identifying the mutations that cause cancer.

But despite huge advances in the development of sequencing technologies to identify these hereditary risk factors, traditional DNA sequencing technologies often fail to identify the hereditary mutations responsible for their disease. 

To change this and bring new hope to these patients, the Terry Fox Research Institute and the Marathon of Hope Cancer Centres Network will be funding a team of researchers led by Dr. George Zogopoulos at the Research Institute of the McGill University Health Centre, who will be piloting the use of a new technology known as long-read sequencing to uncover these elusive genetic mutations associated with hereditary cancer.

"Our study aims to test whether this advanced sequencing technology can identify DNA mutations in genes linked to hereditary cancer that may have been overlooked by conventional methods," explains Dr. Zogopoulos. "We are focusing on patients from our pancreas and gastrointestinal cancer registries who are at the highest risk for having these hidden genetic factors." 

The project has selected 150 patients from a larger cohort, chosen specifically for their potential to reveal critical insights into cancer predisposition. By applying long-read sequencing to their germline DNA, the researchers hope to uncover pathogenic (disease-associated) alterations in cancer susceptibility genes that short-read sequencing technologies may have missed.

"This could revolutionize our understanding of cancer predisposition," says Dr. Zogopoulos. "Identifying pathogenic variants can direct personalized treatments for cancer patients and has significant implications for their relatives, who may also be at risk."

Identifying pathogenic germline variants not only informs treatment strategies for patients but also helps assess the cancer risk for their families. That means, relatives who carry these variants could also access prevention and early detection measures.

That is why the team will work closely with the Return of Results Working Group of the Marathon of Hope Cancer Centres Network, which is already working on a strategy to harmonize the communication of these hereditary cancer risk findings across Canada. This new technology, paired with the communication strategy being developed by this group, could be the key to the creation of new screening protocols for patients at a high-risk of developing cancer, setting the stage for earlier detection of disease, which is associated with better outcomes and quality of life.

"This project underscores the importance of advanced genomic technologies in cancer care," adds Dr. Zogopoulos. "By enhancing our ability to identify genetic risks, we are moving closer to more effective, personalized cancer management for patients and their families." 

All sequencing for this project will be done at the McGill Genome Centre in Montreal and Canada’s Michael Smith Genome Sciences Centre in Vancouver.

"Long-read sequencing holds great promise in uncovering the mysteries of hereditary cancer predisposition," say Drs. Ioannis Ragousis and Marco Marra, who are leading the sequencing efforts in Montreal and Vancouver respectively. "Working together to harmonize how we use this innovative technology across the country is a huge step forward in seeing how we can incorporate it effectively for the benefit of cancer patients."