RESUMO
PURPOSE: Genetically predisposed breast cancer (BC) patients represent a minor but clinically meaningful subgroup of the disease, with 25% of all cases associated with actionable variants in BRCA1/2. Diagnostic implementation of next-generation sequencing (NGS) resulted in the rare identification of BC patients with double heterozygosity for deleterious variants in genes partaking in homologous recombination repair of DNA. As clinical heterogeneity poses challenges for genetic counseling, this study focused on the occurrence and clinical relevance of double heterozygous BC in South Africa. METHODS: DNA samples were diagnostically screened using the NGS-based Oncomine™ BRCA Expanded Research Assay. Data was generated on the Ion GeneStudio S5 system and analyzed using the Torrent Suite™ and reporter software. The clinical significance of the variants detected was determined using international variant classification guidelines and treatment implications. RESULTS: Six of 1600 BC patients (0.375%) tested were identified as being bi-allelic for two germline likely pathogenic or pathogenic variants. Most of the variants were present in BRCA1/2, including two founder-related small deletions in three cases, with family-specific variants detected in ATM, BARD1, FANCD2, NBN, and TP53. The scientific interpretation and clinical relevance were based on the clinical and tumor characteristics of each case. CONCLUSION: This study increased current knowledge of the risk implications associated with the co-occurrence of more than one pathogenic variant in the BC susceptibility genes, confirmed to be a rare condition in South Africa. Further molecular pathology-based studies are warranted to determine whether clinical decision-making is affected by the detection of a second pathogenic variant in BRCA1/2 and TP53 carriers.
RESUMO
Genomic researchers face an ethical dilemma regarding feedback of individual results generated from genomic studies. In the African setting, genomic research is still not widely implemented and, coupled with this, the limited African-specific guidelines on how to feedback on individual research findings. A qualitative study was performed to assess participants' expectations and preferences regarding the feedback of secondary findings from genomic research. Participants were parents of children with a developmental disorder, enrolled in the Deciphering Developmental Disorders in Africa (DDD-Africa) research project, and were purposefully selected. Three deliberative focus group discussions were conducted with 14 participants. Each deliberative focus group consisted of two separate audio-recorded interviews and presented different case scenarios for different types of secondary findings that could be theoretically detected during genomic research. We aimed to explore participants' preferences for the extent, nature, timing, and methods for receiving individual study results, specifically pertaining to secondary findings. Thematic content analysis was done, with a deductive approach to coding. Four themes emerged which included participants' perception of readiness to receive secondary findings, queries raised around who has access to research findings and feedback of findings consent, responsibilities of the researcher, and reasons for not wanting/wanting secondary findings. Overall, participants expressed that they want to receive feedback on secondary findings irrespective of disease severity and treatment availability. Lifestyle changes, early prevention or treatment, impact on future generations, and preparedness were strong motivations for wanting feedback on results. Participants felt that when the research involved minors, it was the parents' right to receive results on behalf of their children. This study provides new insights into participants' preferences around feedback on genomic research results and could serve as an important basis for creating guidelines and recommendations for feedback on genomic results in the African context.
