Researchers at McGill University have discovered a centuries-old genetic mutation that helps to explain why some French‑Canadians in Quebec are at an elevated risk of pancreatic cancer. Until quite recently, standard genetic tests have not been able to identify this "jumping gene" cause.
The findings, published in the Journal of Medical Genetics, suggest better-targeted genetic testing could help identify people at higher cancer risk who were previously missed.
History's imprint on the genome
Quebec's French-Canadian population descends from a relatively small number of settlers who arrived from France in the 1600s. Over generations, some rare genetic changes became more common, a phenomenon known as the founder effect.
"This population history creates unique opportunities to study inherited disease, since a small number of "founder" mutations account for a significant fraction of all hereditary cases," said William Foulkes, Distinguished James McGill Professor in McGill's Departments of Medicine, Oncology, and Human Genetics.
In this case, the inherited mutation is caused by a "jumping gene," a piece of DNA that can copy itself and insert into new places in the genome. When it inserts into the ATM gene, the disruption interferes with DNA repair, a process known to increase cancer risk.
Based on genetic analyses, the team estimates the mutation arose about 300 years ago, roughly 10 to 11 generations back, probably during the early settlement of New France, or shortly before.
Rare mutation, common in pancreatic cancer
In the French-Canadian population of Quebec, the authors found the mutation was present in about 2 per cent of pancreatic cases, compared with about 0.2 per cent of unaffected people, a 10-fold difference. It was also over-represented in French-Canadian women with breast cancer, suggesting it increases breast cancer risk as well. The results are based on patient samples from the Quebec Pancreas Cancer Study and population data from CARTaGENE,
"Although it is rare in the general population, it is strongly enriched in pancreatic cancer cases. That's a significant difference in relative risk," said co-author George Zogopoulos, Professor of Surgery and Oncology at McGill and surgeon at the McGill University Health Centre. "This means it may be possible to identify people at higher risk by testing for this variant."
Toward more targeted testing
The variant was previously missed by standard genetic testing because older methods often failed to detect this type of DNA change. New sequencing technologies are now making detection possible.
"There may be an opportunity to develop a panel that looks for a small number of key cancer‑related founder mutations," said first author Yifan Wang, who conducted this work as a resident and PhD student at McGill. "That could help identify people at higher risk earlier." She added that people who underwent genetic testing five to 10 years ago may benefit from re‑evaluation through genetic counselling.
About the study
"ATM c.7374_7375insAlu is a French-Canadian founder pathogenic variant associated with predisposition to pancreatic and breast cancer," by Yifan Wang, George Zogopoulos, Simon Gravel, William Foulkes et al., was published in the Journal of Medical Genetics.
The study was funded by the Canadian Institutes of Health Research and Fonds de recherche du Québec - Santé and the Michal & Renata Hornstein Career Award for Surgical Excellence.
