frican human genome research is advancing rapidly, owing to falling sequencing costs and international interest in African genomic data: the diversity of African genomes can provide novel insights into biological and etiological mechanisms, thereby promoting diagnostic, prognostic and therapeutic advances for populations in Africa and the rest of the world 1,2. Conducting genomic research in Africa can be logistically challenging 3,4 , but equally challenging is recruiting African participants-many of whom have knowledge-and/or poverty-related vulnerabilities 5,6-while ensuring that they are properly informed and truly consenting, and that they retain their autonomy and agency (examples in refs. 5,7-12). Dynamic consent models, such as those using ongoing engagement through online media 13,14 , ensure autonomy and choice for participants. However, these models cannot be implemented in many African environments, owing to suboptimal internet and smartphone access, and poor digital literacy. In broad-consent models, participants consent to all future use of their samples under the oversight of an access committee, but this consent comes at the cost of the autonomy and individual preferences of participants 10,15. Tiered informed consent addresses these challenges by providing detailed information about the intended specimen/data use and storage, thus enabling participants to individually select a level of specimen and/or data sharing through responses to specific questions 10,16-18. The launch of the H3Africa genotyping chip, with 2.7 million African-specific genomic variants 19 , has increased opportunities for meta-analyses combining multiple cohorts of African participants. To undertake such studies with an ethical mandate, research participants must be properly informed, and their data/ sample-use preferences must be accurately understood, faithfully recorded and implemented with integrity. We propose a framework for undertaking ethically sound, tiered-informed-consent processes in Africa, which provides a comprehensive guide on compiling participant information and an informed-consent template for capturing each participant's consent information and mapping it to data-use ontologies.
Introduction: Obtaining informed consent from study participants and disseminating the findings responsibly is a key principle required for ethically conducted clinical and genetic research. Reports from African researchers providing feedback on insights gained during the return of whole exome sequencing (WES) results to breast cancer patients treated in resource-limited settings is lacking. Aim:The empirical process used to fill this gap in relation to BRCA1/2 variant detection using WES provided unique insights incorporated into a pathology-supported genetic testing algorithm for return of research results to Kenyan breast cancer patients. Methods:The Informed consent form approved by the Moi Teaching and Referral Hospital in Kenya was adopted from a translational research study conducted in South Africa. Initially, the informed consent process was piloted in 16 Kenyan female patients referred for breast surgery, following a community-based awareness campaign. A total of 95 female and two male breast cancer patients were enrolled in the study from 2013 to 2016. Immunohistochemistry (IHC) results of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status were obtained from hospital records. DNA of patients with a family history of cancer was extracted from saliva and screened for pathogenic variants in the BRCA1/2 genes as the first step using WES.Results: Ten patients approached for participation in this study declined to sign the informed consent form. Data on IHC used as a proxy for molecular subtype were available in 8 of 13 breast cancer patients (62%) with a family history of cancer. Five BRCA1/2 variants of uncertain clinical significance were detected, as well as a pathogenic BRCA2 variant (c.5159C > A; S1720 * ) in a female patient eligible for return of WES results.
Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.
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