Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112, USA.
Louisiana Tumor Registry, Louisiana State University Health Sciences Center, School of Public Health, 2020 Gravier Street, New Orleans, LA 70112, USA.
Int J Environ Res Public Health. 2019 Mar 23;16(6):1055. doi: 10.3390/ijerph16061055.
Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.
近年来高通量基因分型技术的进步和癌症基因组的下一代测序技术的兴起，使得与乳腺癌发病风险增加相关的胚系突变和驱动疾病的获得性体细胞突变的发现成为可能。新出现的证据表明，胚系突变可能与体细胞突变相互作用，从而促进癌症的发生。然而，三阴性乳腺癌（TNBC）中胚系和体细胞改变之间的可能致癌相互作用和协同作用尚未得到描述。本研究的目的是研究 TNBC 中胚系和体细胞突变相关基因之间可能的致癌相互作用和协同作用。我们的工作假设是，与乳腺癌发病风险增加相关的含有胚系突变的基因也含有在肿瘤发生过程中获得的体细胞突变，并且这些基因在功能上是相关的。我们进一步假设，TNBC 源自含有胚系和体细胞突变的基因之间以及这些相互作用的遗传因素之间的复杂相互作用，并认为这些相互作用的遗传因素影响整个分子网络和生物学途径，从而推动疾病的发展。我们通过整合来自全基因组关联研究（GWAS）的胚系突变信息和来自癌症基因组图谱（TCGA）的 TNBC 的体细胞突变信息，使用来自 110 名 TNBC 患者和 113 名对照的基因表达数据，对这一假设进行了测试。我们发现了一个包含胚系和体细胞突变的 237 个功能相关基因的特征。我们发现了富含胚系和体细胞突变的分子网络和生物学途径。最主要的途径包括遗传性乳腺癌和在 DNA 损伤反应信号通路中的作用。总之，这是首次大规模和全面的分析，描绘了 TNBC 中胚系和体细胞突变相关基因之间以及这些基因之间可能的致癌相互作用和协同作用。遗传和体细胞突变以及本研究中发现的基因，需要在不同的种族群体中进行实验功能验证。功能验证的遗传和体细胞变异将对开发新的精准预防策略和发现 TNBC 的预后标志物具有重要意义。
