Department of Molecular Biology and Biotechnology, University of Dar es Salaam, Dar es Salaam, Tanzania.
Mbeya College of Health and Allied Sciences, University of Dar es Salaam, Mbeya, Tanzania.
Cancer Med. 2023 Feb;12(3):3395-3409. doi: 10.1002/cam4.5091. Epub 2022 Jul 31.
Growing prevalence and aggressiveness of breast cancer (BC) among East African women strongly indicate that the genetic risk factor implicated in the etiology of the disease may have a key role. Germline pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) are known to increase the lifetime risk of BC. This study investigated the prevalence and spectrum of germline single nucleotide variant/insertion and deletion (SNV/indel), and copy number variations (CNVs) in BRCA1/2 among Tanzanian BC patients, and evaluated the associations of identified variants with patient's socio-demographic and histopathological characteristics.
One hundred BC patients were examined for BRCA1/2 variants using next-generation sequencing (NGS). Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay were performed for the confirmation of SNV/indel and CNVs, respectively.
Six germline SNV/indel pathogenic variants were detected from six unrelated patients. Five of these variants were identified in BRCA1, and one in BRCA2. We also identified, in one patient, one variant of uncertain clinical significance (VUS). CNV was not detected in any of the BC patients. Furthermore, we found that in our cohort, BRCA1/2 variant carriers were triple-negative BC patients (p = 0.019).
Our study provides first insight into BC genetic landscape by the use of NGS in the under-represented East African Tanzanian populations. Our findings support the importance of genetic risk factors in BC etiology in Tanzania and showed a relatively high overall prevalence (6%) of germline BRCA1/2 pathogenic variants in BC patients. Therefore, our results indicate that BRCA1/2 pathogenic variants may well contribute to BC incidence in Tanzania. Thus, the identification of frequent variants in BRCA1/2 genes will enable implementation of rapid, inexpensive population-specific BRCA1/2 genetic testing, particularly for triple-negative BC patients known for their high prevalence in Tanzania. This will, in turn, greatly contributes to provide effective therapeutic strategies.
东非国家的乳腺癌（BC）发病率和侵袭性日益增高，强烈表明与疾病病因相关的遗传风险因素可能发挥关键作用。BRCA1 和 BRCA2（BRCA1/2）种系致病性变异可显著增加终生 BC 发病风险。本研究调查了坦桑尼亚 BC 患者 BRCA1/2 种系单核苷酸变异/插入缺失（SNV/indel）和拷贝数变异（CNV）的流行率和谱，并评估了所识别变异与患者社会人口统计学和组织病理学特征的相关性。
采用下一代测序（NGS）对 100 例 BC 患者进行 BRCA1/2 变异检测。采用 Sanger 测序和多重连接依赖性探针扩增（MLPA）法分别对 SNV/indel 和 CNV 进行确认。
从 6 名无血缘关系的患者中检测到 6 种种系 SNV/indel 致病性变异。其中 5 种变异位于 BRCA1，1 种位于 BRCA2。我们还在 1 名患者中发现了 1 种意义不明的变异（VUS）。在任何 BC 患者中均未检测到 CNV。此外，我们发现，在我们的队列中，BRCA1/2 变异携带者为三阴性 BC 患者（p=0.019）。
本研究首次利用 NGS 技术在代表性不足的东非坦桑尼亚人群中对 BC 遗传图谱进行了研究。我们的发现支持遗传因素在坦桑尼亚 BC 发病机制中的重要性，并显示了 BC 患者中种系 BRCA1/2 致病性变异的总体较高流行率（6%）。因此，我们的结果表明，BRCA1/2 致病性变异可能是导致坦桑尼亚 BC 发病率升高的原因之一。因此，识别 BRCA1/2 基因中的常见变异将能够实现快速、经济的基于人群的 BRCA1/2 基因检测，特别是对在坦桑尼亚高发的三阴性 BC 患者。这反过来将极大地有助于提供有效的治疗策略。
