Incorporating functional genomics into the pathology-supported genetic testing framework implemented in South Africa: A future view of precision medicine for breast carcinomas

IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Claudia Christowitz , Daniel W. Olivier , Johann W. Schneider , Maritha J. Kotze , Anna-Mart Engelbrecht
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引用次数: 0

Abstract

A pathology-supported genetic testing (PSGT) framework was established in South Africa to improve access to precision medicine for patients with breast carcinomas. Nevertheless, the frequent identification of variants of uncertain significance (VUSs) with the use of genome-scale next-generation sequencing has created a bottleneck in the return of results to patients. This review highlights the importance of incorporating functional genomics into the PSGT framework as a proposed initiative. Here, we explore various model systems and experimental methods available for conducting functional studies in South Africa to enhance both variant classification and clinical interpretation. We emphasize the distinct advantages of using in vitro, in vivo, and translational ex vivo models to improve the effectiveness of precision oncology. Moreover, we highlight the relevance of methodologies such as protein modelling and structural bioinformatics, multi-omics, metabolic activity assays, flow cytometry, cell migration and invasion assays, tube-formation assays, multiplex assays of variant effect, and database mining and machine learning models. The selection of the appropriate experimental approach largely depends on the molecular mechanism of the gene under investigation and the predicted functional effect of the VUS. However, before making final decisions regarding the pathogenicity of VUSs, it is essential to assess the functional evidence and clinical outcomes under current variant interpretation guidelines. The inclusion of a functional genomics infrastructure within the PSGT framework will significantly advance the reclassification of VUSs and enhance the precision medicine pipeline for patients with breast carcinomas in South Africa.

将功能基因组学纳入南非实施的病理支持基因检测框架:乳腺癌精准医疗的未来展望
南非建立了病理支持基因检测(PSGT)框架,以改善乳腺癌患者获得精准医疗的机会。然而,随着基因组规模的下一代测序技术的使用,意义不确定的变异(VUS)的频繁出现,给患者返回结果造成了瓶颈。本综述强调了将功能基因组学纳入 PSGT 框架作为一项拟议举措的重要性。在此,我们探讨了在南非开展功能研究的各种模型系统和实验方法,以加强变异分类和临床解释。我们强调了使用体外、体内和转化体外模型提高精准肿瘤学有效性的独特优势。此外,我们还强调了蛋白质建模和结构生物信息学、多组学、代谢活性检测、流式细胞仪、细胞迁移和侵袭检测、管形成检测、变异效应多重检测以及数据库挖掘和机器学习模型等方法的相关性。选择合适的实验方法在很大程度上取决于所研究基因的分子机制和 VUS 的预测功能效应。然而,在就 VUS 的致病性做出最终决定之前,必须根据现行的变异解释指南评估功能证据和临床结果。将功能基因组学基础设施纳入 PSGT 框架将极大地推动 VUS 的重新分类,并加强南非乳腺癌患者的精准医疗管道。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
12.20
自引率
1.90%
发文量
22
审稿时长
15.7 weeks
期刊介绍: The subject areas of Reviews in Mutation Research encompass the entire spectrum of the science of mutation research and its applications, with particular emphasis on the relationship between mutation and disease. Thus this section will cover advances in human genome research (including evolving technologies for mutation detection and functional genomics) with applications in clinical genetics, gene therapy and health risk assessment for environmental agents of concern.
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