Oosthuizen Jaco, Kotze Maritha J, Van Der Merwe Nicole, Myburgh Ettienne J, Bester Phillip, van der Merwe Nerina C
Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
Division of Human Genetics, National Health Laboratory Service, Universitas Hospital, Bloemfontein, South Africa.
Front Oncol. 2021 Feb 12;10:619469. doi: 10.3389/fonc.2020.619469. eCollection 2020.
Breast cancer patients historically benefitted from population-based genetic research performed in South Africa, which led to the development of founder-based diagnostic tests. With the advent of next-generation sequencing (NGS) technologies, the clinical utility of limited, targeted genetic assays were questioned. The study focused on mining NGS data obtained from an extensive single-institution NGS series (n=763). The aims were to determine (i) the prevalence of the most common recurrent/founder variants in patients referred for NGS directly; and (ii) to explore the data for inferred haplotypes associated with previous and potential new recurrent/founder variants. The identification of additional founder variants was essential for promoting and potentially advancing to rapid founder-based point-of-care (POC) technology as a time- and cost-effective alternative. NGS revealed actionable variants in 11.1% of patients tested ( - 4.7%; - 6.4%), of which 22.4% represented variants currently screened for using first-tier targeted genetic testing. A retrospective investigation into the overall mutation-positive rate for an extended cohort (n=1906), which included first-tier test results, revealed that targeted genetic testing identified 74% of all pathogenic variants. This percentage justified the use of targeted genetic testing as a first-tier assay. Inferred haplotype analysis confirmed the founder status of c.5771_5774del (rs80359535) and c.7934del (rs80359688) and revealed an additional African founder variant ( c.582G>A - rs80358810). A risk-benefit analysis using a questionnaire-based survey was performed in parallel to determine genetic professionals' views regarding POC testing. This was done to bridge the clinical implementation gap between haplotype analysis and POC testing as a first-tier screen during risk stratification of breast and ovarian cancer patients. The results reflected high acceptance (94%) of POC testing when accompanied by genetic counselling. Establishing the founder status for several recurrent variants across ethnic groups supports unselected use of the BRCA POC assay in all SA breast/ovarian cancer patients by recent local and international public health recommendations. Incorporating POC genotyping into the planned NGS screening algorithm of the Department of Health will ensure optimal use of the country's recourses to adhere to the set standards for optimal care and management for all breast cancer patients.
从历史上看，南非开展的基于人群的基因研究使乳腺癌患者受益，这推动了基于始祖突变的诊断检测方法的发展。随着下一代测序（NGS）技术的出现，有限的靶向基因检测的临床实用性受到质疑。该研究聚焦于挖掘从一个大型单机构NGS系列（n = 763）中获得的NGS数据。其目的是确定：（i）直接接受NGS检测的患者中最常见的复发性/始祖突变的患病率；以及（ii）探索与先前和潜在的新复发性/始祖突变相关的推断单倍型数据。识别额外的始祖突变对于推动并可能发展基于始祖突变的快速即时护理（POC）技术至关重要，因为它是一种具有时间和成本效益的替代方法。NGS在11.1%的检测患者中发现了可采取行动的突变（-4.7%；-6.4%），其中22.4%代表目前使用一线靶向基因检测筛查的突变。对一个扩大队列（n = 1906）的总体突变阳性率进行回顾性调查，其中包括一线检测结果，发现靶向基因检测识别出了所有致病变异的74%。这一比例证明了将靶向基因检测用作一线检测方法的合理性。推断单倍型分析证实了c.5771_5774del（rs80359535）和c.7934del（rs80359688）的始祖突变状态，并发现了另一个非洲始祖突变（c.582G>A - rs80358810）。同时，通过基于问卷的调查进行了风险效益分析，以确定基因专业人员对POC检测的看法。这样做是为了弥合单倍型分析与POC检测作为乳腺癌和卵巢癌患者风险分层中的一线筛查之间的临床实施差距。结果显示，在有基因咨询的情况下，POC检测的接受度很高（94%）。确定不同种族中几种复发性突变的始祖突变状态，支持了近期本地和国际公共卫生建议中对所有南非乳腺癌/卵巢癌患者无差别使用BRCA POC检测方法。将POC基因分型纳入卫生部计划的NGS筛查算法中，将确保最佳利用该国资源，以符合为所有乳腺癌患者提供最佳护理和管理的既定标准。
