Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, 13, Place Pasteur-BP 74, 1002, Tunis, Tunisia.
Laboratory of Bioinformatics, Biomathematics and Biostatistics, LR16IPT09, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.
J Transl Med. 2018 Jun 7;16(1):158. doi: 10.1186/s12967-018-1504-9.
A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking.
A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk.
Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein-protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6.
In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.
长期以来，乳腺癌家族史被认为存在导致这种疾病的遗传事件。与西方人群相比，在北非的乳腺癌家族中观察到许多特定的流行病因学特征。尽管存在这些特殊性，但北非进行的大多数乳腺癌遗传学研究仍然仅限于对 BRCA1 和 BRCA2 基因的研究。因此，缺乏来自当地患者的全外显子或全基因组水平的综合数据。
使用基于家族的方法对七个突尼斯乳腺癌家庭进行了全外显子组测序（WES）。我们将分析重点放在 BC-TN-F001 家族上，该家族包括两个受影响的成员，已使用 WES 进行测序。在 BC-TN-F001 中鉴定出的相关变体已使用 Sanger 测序进行了验证。然后，我们通过将我们的结果与其他 WES 研究的结果相结合，进行综合分析，以确定新鉴定基因的遗传传递模型。构建生物网络和蛋白质-蛋白质相互作用分析，以破译可能导致这些基因在乳腺癌风险中发挥作用的分子机制。
已完成测序、过滤策略和验证分析。对于 BC-TN-F001，未在已知的乳腺癌基因上鉴定出有害突变。然而，在其他候选基因上鉴定出 373 个杂合的、外显子的和罕见的变体。应用多种过滤器后，选择了 12 个相关的高危变体。我们的结果表明，这些变体似乎以家族特异性模型遗传。在对已报道的 WES 研究进行彻底分析后，证实了这一假设。丰富的生物学过程和蛋白质-蛋白质相互作用网络导致鉴定出四个新的乳腺癌候选基因，即 MMS19、DNAH3、POLK 和 KATB6。
在对突尼斯乳腺癌患者进行的首次 WES 应用中，我们强调了下一代测序技术在鉴定新的乳腺癌候选基因方面的作用，这可能为乳腺癌发生的生物学机制提供新的见解。我们的研究结果表明，非 BRCA 家族的乳腺癌易感性可能具有种族和/或家族特异性。
