Analyzing the genetic landscape of French-Canadian hereditary breast cancer women that carry pathogenic BRCA1 or BRCA2 variants

Family history of breast cancer (BC) is a factor that increases an individual’s risk for BC owing to the transmission of disease-causing alleles. Pathogenic variants in BRCA1 and BRCA2 are commonly found in women that are at a high-risk of developing BC and confer estimated lifetime risks ranging between 65-79% and 61-77%, respectively. Similar to many other BC predisposing genes (BCPGs) such as ATM, CHEK2 and PALB2, BRCA1/BRCA2 play an important role in the maintenance of genomic integrity through their involvement in the homologous recombination pathway. While pathogenic variants in BRCA1/BRCA2 are found at a frequency of less than 1/40 people in the general population, founder populations, such as the French-Canadians (FC) of Quebec, have an enrichment of pathogenic variants in BRCA1/BRCA2 due to common ancestry. Our lab identified two hereditary BC (HBC) cases that harbour pathogenic variants in two BCPGs, which I refer to as a genetic collision event. The biological implications of this phenomenon are unknown due to the paucity of cases that have been reported. Given the role of known BCPGs in DNA repair pathways, I performed bioinformatic analyses on whole exome sequencing data from 58 FC HBC cases that harbour pathogenic variants in BRCA1/BRCA2 to determine whether they harbour pathogenic variants in other genes involved in DNA repair pathways. I have identified eight candidate variants in ATM, BARD1, CHEK2, ERCC6, MLH1, MUTYH and NSMCE2. I screened these candidate variants in other FC study groups consisting of HBC cases, regardless of BRCA1/BRCA2-carrier status, and cancer-free individuals and identified additional carriers in two cancer-free males (2/119, 1.7%) and one cancer-free female (1/52, 1.9%). To better elucidate the effects of genetic collision events, I reviewed the published peer reviewed literature for other BC cases in which genetic collision events can be observed and compared their clinical features with single variant BC cases from our FC study groups. I found that a significantly higher frequency of double variant BC cases developed multiple primary tumours in comparison to single variant BC cases. Therefore, these findings demonstrate that FC HBC cases that harbour pathogenic variants in BRCA1/BRCA2 also carry co-occurring pathogenic variants in other DNA repair pathway genes that may influence disease characteristics

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