Ovarian cancer affects approximately 3000 women per year in Canada. Although most cases are sporadic, there are hereditary forms of ovarian cancer that are largely attributed to mutations in the BRCA1 and BRCA2 genes, which are also involved in breast cancer. However, some families with no known cancer predisposing genes develop multiple cases of ovarian cancer, suggesting that mutations in unknown genes remain to be discovered.
With this in mind, scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) set out to investigate new genes that could be associated with a risk of ovarian cancer. Their findings, published in Genome Medicine, show that a mutation in the FANCI gene is more common in ovarian cancer patients with a family history of ovarian cancer than in cancer-free people, suggesting that it may influence the risk of developing that cancer. The study, conducted in sample populations of Canadians of French descent in Quebec, Canadians of diverse origins and Australian populations, may influence the genetic screening of women for ovarian cancer, a disease for which few therapies are available, leading to a survival rate of less than 30 per cent.
“Using bioinformatics, we targeted genes that play a role in DNA repair, such as BRCA1 and BRCA2, and this is what led us to the FANCI gene,” explains Dr. Patricia Tonin, principal investigator of the study and senior scientist in the Cancer Research Program at the RI-MUHC. “This study emphasizes the importance of pursuing variants during the gene discovery phase, especially when plausible gene candidates are revealed by analyses of defined cancer families.”
The researchers first looked at two sisters who had ovarian cancer and a family history of ovarian cancer, but who did not have BRCA1 or BRCA2 pathogenic variants. Genetic testing using next generation sequencing, performed with the support of Dr. Jiannis Ragoussis, Head of Genome Sciences at the McGill Genome Centre and professor in the Department of Human Genetics at McGill, determined that they carried a mutation in the FANCI gene, which shares some characteristics with the BRCA1 and BRCA2 genes.
The researchers then sequenced familial cases of ovarian cancer and compared variant frequencies in people with and without ovarian cancer in a population pool of French Canadians from Quebec. This population has a unique genetic landscape due to sharing genetic information from common ancestors that can be traced back to the early populations that emigrated from Western Europe and populated Quebec since the 1600s.
“Due to a relatively few number of ancestors, rapid expansion and geographic isolation of the small founding French population of Quebec during the period from 1608 to 1760, a loss of genetic variation has occurred, resulting in subsequent waves of expansion of specific variants,” explains Caitlin Fierheller, the first author of the study, who is a PhD candidate in the Department of Human Genetics at McGill and a trainee at the RI-MUHC. “Therefore, candidate variants for ovarian cancer may be more readily identified in cancer cases versus cancer-free controls in French Canadians, in contrast to the general population.”
The research team found that the FANCI mutation they had identified was more common in people with ovarian cancer. Because of the nature and frequency of the FANCI variants found in Quebec, the team wanted to gather additional evidence that the mutation was indeed producing an aberrant protein. They reached out to a molecular biologist specializing in the biochemistry of DNA repair pathways who was already studying the biology of FANCI, Dr. Jean-Yves Masson, professor in the Department of Molecular Biology, Medical Biochemistry and Pathology at Université Laval and researcher at the CHU de Québec-Université Laval Research Centre, Oncology axis. Dr. Masson tested the variant and found that it was indeed an abnormally functioning protein.
The team continued the investigation with Canadians of non-French origin, as well as with an Australian population, and came to the same conclusion.
“Our results showed that the FANCI variant we discovered is present in different populations and that it plays a role in the risk of ovarian cancer,” says Dr. Tonin, who is also a professor in the Departments of Medicine and Human Genetics at McGill University.
The study authors also point out that other genetic, environmental or host factors could affect the risk of ovarian cancer in carriers of FANCI variants. For example, their work suggests that FANCI mutation carriers who have taken oral contraceptives have not yet developed ovarian cancer.
Replication studies are needed to confirm these results in larger groups worldwide. In addition, studies to clarify the cancer risk conferred by FANCI variants are required to inform medical genetic screening practices for managing risk and ovarian cancer.
About the study
The study A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene was conducted by Caitlin T Fierheller, Laure Guitton-Sert, Wejdan M Alenezi, Timothée Revil, Kathleen K Oros, Yuandi Gao, Karine Bedard, Suzanna L Arcand, Corinne Serruya, Supriya Behl, Liliane Meunier, Hubert Fleury, Eleanor Fewings, Deepak N Subramanian, Javad Nadaf, Jeffrey P Bruce, Rachel Bell, Diane Provencher, William D Foulkes, Zaki El Haffaf, Anne-Marie Mes-Masson, Jacek Majewski, Trevor J Pugh, Marc Tischkowitz, Paul A James, Ian G Campbell, Celia M T Greenwood, Jiannis Ragoussis, Jean-Yves Masson and Patricia N Tonin.
This research was made possible thanks to funding from The Canadian Institute for Health Research, Cancer Research Society, Ovarian Cancer Canada, Canadian Foundation for Innovation – Major Science Initiatives Fund, Genome Canada, Fonds de recherche du Québec-Santé, Quebec Breast Cancer Foundation and the Department of Medicine at McGill.