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, including UBC’s Dr. Marco Marra (Michael Smith Laboratories, Department of Medical Genetics), Intan Schrader (Medical Genetics), Janessa Laskin (Medical Oncology), and Daniel Renouf (Medical Oncology).

The pan-Canadian team, led by Dr. George Zogopoulos at the Research Institute of the McGill University Health Centre, will pilot the use of a new technology known as long-read sequencing to uncover these elusive genetic mutations associated with hereditary cancer.

“Identifying genomic alterations in normal DNA that predispose to cancer can lead to early detection of cancer, at a stage when it can be cured,” says Dr. Marco Marra. “Our team is thrilled to be part of this exciting research study led by Dr. Zogopoulos, which brings together colleagues from Montreal, Toronto and Vancouver to evaluate whether newer sequencing technologies can enhance our ability to find these cancer predisposing changes.” 

The project has selected 150 patients from a larger cohort, chosen specifically for their potential to reveal critical insights into cancer predisposition.

“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.”

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.”

 

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

Team: George Zogopoulos, Research Institute of the McGill University Health Centre (RI-MUHC)/Goodman Cancer Institute (GCI) (lead); Ioannis Ragousis, McGill Genome Centre (MGC),  Guillaume Bourque, McGill Genome Centre (MGC), Steven Gallinger, Ontario Institute for Cancer Research (OICR), Robert Grant, Princess Margaret Cancer Centre (PMCC) , Erica Tsang, Princess Margaret Cancer Centre (PMCC), Intan Schrader, BC Cancer/Michael Smith Genome Sciences Centre (GSC) , Marco Marra, University of British Columbia Medical Genetics and Michael Smith Laboratories / Canada’s Michael Smith Genome Sciences Centre (GSC), Janessa Laskin, BC Cancer/Michael Smith Genome Sciences Centre (GSC), Daniel Renouf, BC Cancer/Michael Smith Genome Sciences Centre (GSC)

 

A version of this story was originally shared by the Marathon of Hope Cancer Centres Network