Familial cases of ovarian cancer are often associated with mutations in the BRCA1 and BRCA2 genes. However, other cases cannot be attributed to known ovarian cancer-associated genes, indicating there could be other responsible gene variants. New findings from scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) in Montreal, Canada, revealed that mutations in the FANCI gene were more common in familial ovarian cancer cases than in people without cancer.
'Using bioinformatics, we targeted genes that play a role in DNA repair... this is what led us to the FANCI gene,' said Dr Patricia Tonin, senior scientist in the Cancer Research Programme at the RI-MUHC. 'This study emphasises the importance of pursuing variants during the gene discovery phase, especially when plausible gene candidates are revealed by analyses of defined cancer families'.
The study, published in Genome Medicine, used French Canadians from Quebec because this population has relatively few ancestors after experiencing geographical isolation when the early populations emigrated from Western Europe to Quebec in the early 1600s, leading to a loss of genetic variation. Since then rapid growth in the population has resulted in an expansion of specific variants and as such, gene variants for ovarian cancer may be more easily found in French Canadian cancer patients, as opposed to other populations.
First, the FANCI mutation was identified in two sisters with ovarian cancer, who had a family history of the condition but did not carry BRCA1 and BRCA2 mutations. Then, the findings were supported with next-generation DNA sequencing, known as whole exome sequencing. Next, a population pool of French Canadians with and without familial cases of ovarian cancer were sequenced. This confirmed that the FANCI mutation was more common in ovarian cancer subjects. Finally, Canadians of non-French origins and Australians were tested, corroborating the findings.
'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,' concluded Dr Tonin.
In healthy cells, the FANCI gene is involved in a DNA repair pathway that also involves BRCA1 and BRCA2 function. Further tests showed that the FANCI gene variant produced an abnormal protein. The scientists also discovered that cell lines with the FANCI mutation were sensitive to the cancer drug cisplatin but not to olaparib, which is in contrast to ovarian cancer patients with mutations in BRCA1 and BRCA2 (see BioNews 1092).
Other genetic, environment or host factors could also contribute to the risks of ovarian cancer. For example, the oral contraceptive pill use was associated with less risk of developing ovarian cancer for FANCI mutation carriers, known to significantly impact the lifetime risk of ovarian cancer.
Genetic screening protocols for ovarian cancer may be influenced by these findings. Although, follow-up studies are needed in larger populations worldwide.