Song Bin, Cui Heyang, Li Yaoping, Cheng Caixia, Yang Bin, Wang Fang, Kong Pengzhou, Li Hongyi, Zhang Ling, Jia Zhiwu, Bi Yanghui, Wang Jiaqian, Zhou Yong, Liu Jing, Wang Juan, Zhao Zhenxiang, Zhang Yanyan, Hu Xiaoling, Shi Ruyi, Yang Jie, Liu Haiyan, Yan Ting, Li Yike, Xu Enwei, Qian Yu, Xi Yanfeng, Guo Shiping, Chen Yunqing, Wang Jinfen, Li Guodong, Liang Jianfang, Jia Junmei, Chen Xing, Guo Jiansheng, Wang Tong, Zhang Yanbo, Li Qingshan, Wang Chuangui, Cheng Xiaolong, Zhan Qimin, Cui Yongping
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.
Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
Oncotarget. 2016 Jan 19;7(3):3599-613. doi: 10.18632/oncotarget.6120.
Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy. Esophageal squamous cell carcinoma (ESCC) contains genomic alterations of undefined clinical significance. We aimed to identify mutually exclusive mutations that are frequently detected in ESCCs and characterized their associations with clinical variables.
We analyzed next-generation-sequencing data from 104 ESCCs from Taihang Mountain region of China; 96 pairs were selected for deep target-capture-based validation and analysis of clinical and pathology data. We used model proposed by Szczurek to identify exclusive mutations and to associate these with pathology findings. Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy. Findings were validated in an analysis of samples from 89 patients with ESCC from Taihang Mountain.
We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples. Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes. Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy. In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations.
In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA. These findings might increase our understanding of ESCC development and be used as prognostic factors.
与临床特征相关的复发性基因异常可用于确定患者的预后、选择治疗方案以及预测治疗反应。食管鳞状细胞癌（ESCC）存在一些临床意义尚不明确的基因组改变。我们旨在识别ESCC中经常检测到的相互排斥的突变，并阐明它们与临床变量的关联。
我们分析了来自中国太行山区104例ESCC的二代测序数据；选取96对样本进行基于深度靶向捕获的验证，并分析临床和病理数据。我们使用Szczurek提出的模型来识别排他性突变，并将这些突变与病理结果相关联。采用Cox比例风险模型进行单因素和多因素分析，以检验突变与总生存期及化疗反应之间的关联。研究结果在对来自太行山区89例ESCC患者的样本分析中得到验证。
我们在ESCC样本中发现NOTCH1和PIK3CA突变之间具有统计学意义的相互排斥性。NOTCH1突变与高分化、早期恶性肿瘤以及区域淋巴结转移较少相关。然而，NOTCH1突变患者的生存期比无NOTCH1突变患者短，且对化疗无反应。相反，PIK3CA突变患者比无PIK3CA突变患者对化疗反应更好，生存期更长。
在中国患者ESCC的基因分析中，我们识别出NOTCH1和PIK3CA的相互排斥性突变。这些发现可能会增进我们对ESCC发生发展的理解，并用作预后因素。
