Forouzanfar Narjes, Baranova Ancha, Milanizadeh Saman, Heravi-Moussavi Alireza, Jebelli Amir, Abbaszadegan Mohammad Reza
1 Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
2 School of System Biology, George Mason University, Fairfax, VA, USA.
Tumour Biol. 2017 May;39(5):1010428317699115. doi: 10.1177/1010428317699115.
Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.
食管鳞状细胞癌是所有癌症中致死率最高的癌症之一。其转移特性预示着预后不良和高复发率。一种更先进的识别预测疾病预后的新分子生物标志物的方法是全外显子测序。在此，我们通过全外显子测序报告了食管鳞状细胞癌易感性中Notch信号通路最有效的基因变异。我们分析了9个无关家族性食管鳞状细胞癌家系中的先证者以确定候选基因。提取基因组DNA并进行全外显子测序以生成编码区基因变异的信息。利用生物信息学软件应用来运用统计算法展示蛋白质结构和变异保守性。通过假阳性研究排除多态性区域。对Notch信号通路候选基因进行基因-基因相互作用分析。我们通过广泛的通路导向筛选和功能预测确定了Notch信号通路的新的有害变异，这导致对所有9名患者中的27个候选新突变进行研究。在9名先证者中的5名中检测到含有6B基因突变（一个剪接位点改变）的三核苷酸重复序列，但在任何健康样本中均未检测到，这表明它可能是家族性食管鳞状细胞癌的一个易感因素。值得注意的是，27个新的候选基因突变中的8个（例如表皮生长因子、信号转导子和转录激活子3、MET）以级联方式发挥作用导致细胞存活和增殖。我们的结果表明，含有6B突变的三核苷酸重复序列可能是食管鳞状细胞癌的一个候选易感基因。此外，Notch信号通路的一些基因突变可能是食管鳞状细胞癌的关键促成因素。
