Germline sequence variants contributing to cancer susceptibility in South African breast cancer patients

Thesis (PhD (Bioinformatics))--University of Pretoria, 2022.Breast cancer is increasingly a public health problem worldwide. It is the most commonly diagnosed cancer and the leading cause of cancer deaths in women. Breast cancer incidence and mortality rates are rising in transitioning countries in Africa, with some of the most rapid increases occurring in sub-Saharan Africa. Newly diagnosed breast cancer cases in South Africa accounts for 27.1% of female cancers in 2020, with age-standardized (World) incidence and mortality rates of 52.6 and 16 (per 100,000 women) respectively. Cancer results from a process of genetic changes, some inherited, some induced by environmental exposures and some occurring by chance. Early age of onset and a family history is a hallmark of hereditary breast cancer that is associated with germline variants in the high-penetrance genes, BRCA1 and BRCA2. An association with breast cancer susceptibility has also been reported for a further eleven high- to moderate-penetrance genes (TP53, PALB2, PTEN, STK11, CDH1, ATM, BRIP1, CHEK2, RAD51B, RAD51C, and RAD51D). In addition, pathogenic variants in genes from the mismatch repair pathway (MLH1, MSH2, MSH6 and PMS2) have been identified in breast cancer and ovarian cancer patients. This study screened 165 South African breast cancer patients of African ancestry (self-identified) for the presence of deleterious germline sequence variants in 94 genes associated with hereditary cancer. The patients were unselected for age at diagnosis or family history of cancer. We identified pathogenic/likely pathogenic variants in thirteen patients from genes (ALK, ATM, BRCA1, BRCA2, BUB1B, CHEK2, FANCG,PALB2, RB1 and XPC ). Furthermore, a set of 27 variants of unknown significance was identified and reported that may play an important role in the future of pathogenic variants in the African population. Lastly, fourteen significant non-coding pathogenic variants from upstream, downstream and intergenic introns around the exons were identified using a combination of variant effect, CADD-PHRED and FATHMM-MKL predictions. To our knowledge, only two studies in Africa, one on Nigerian women, and one on women from Uganda and Cameroon, have used multigene panel sequencing to test for germline variants in patients, unselected for family history or age at diagnosis. Although we investigated a relatively small cohort of patients, our study provides some insights towards the genetic breast cancer risk factors in South African women of African ancestry. Further studies of a larger patient cohort is warranted to assess the distribution of variants in clinically relevant cancer susceptibility genes.National research foundationCANSASouth African Medical research councilBiochemistryPhD (Bioinformatics)Unrestricte