Non-BRCA breast cancer predisposing variants identified in Kenyan patients using whole-exome sequencing

Abstract

Background: Breast cancer is a leading cause of cancer-related mortality in women worldwide. This disease is reported to be associated with mutations in several predisposing genes in addition to the long known BRCA1/2. Differences in genetic epidemiology of breast cancer have been observed in people of African ancestry compared to their Caucasian counterparts, with higher mortality burden, early age of disease onset, higher prevalence of Triple Negative subtype that is a more aggressive form of breast cancer. Given these differences and the known African-diverse genetic background, most of the known breast cancer predisposing mutations have been characterized in the Western populations which leaves a knowledge gap in the predisposing mutations within the African populations to explain the observed differences. Only 5-10% of breast cancer are inherited, and germline pathogenic variants in DNA damage repair (DDR) genes BRCA1/2 explain only 10-20% of these cases. This study investigated the spectrum and prevalence of germline variants in 32 non-BRCA DDR pathway genes.

Methods: Bioinformatics analysis of 40 whole-exome sequencing data was performed to identify rare non-synonymous variants. A panel of 32 non-BRCA genes already known to be associated with an increased risk to developing breast cancer was be analyzed to identify both known and potentially novel mutations in non-BRCA breast cancer associated genes among Kenyan women.

Results: A total of 172 mutations classified as either pathogenic or likely pathogenic by clinvar in 19 genes were identified. 95 of these mutations were associated with either familial breast cancer (30 variants) or Hereditary cancer predisposing syndrome (73 variants). This included variants that were found in all 40 of the patients. A list of 22 variants that were either classified as “uncertain significance” or not reported in ClinVar, that had a very high prediction score by 9 prioritization tools is suggested here for further investigations. Eight (8) of these variants have not been reported in any previous studies to our knowledge and have been identified each in only one of the patients.

Conclusion: Although BRCA1 and BRCA2 remain 2 very crucial genes in assessing an individual’s risk to developing breast cancer, it might be very useful incorporating other genes with a high to moderate penetrance in the screening panel. The unique variants observed in this study shed light of the potential gap of mutations specific among the some African populations.