Clinical Research Papers:

Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China

Bin Song, Heyang Cui, Yaoping Li, Caixia Cheng, Bin Yang, Fang Wang, Pengzhou Kong, Hongyi Li, Ling Zhang, Zhiwu Jia, Yanghui Bi, Jiaqian Wang, Yong Zhou, Jing Liu, Juan Wang, Zhenxiang Zhao, Yanyan Zhang, Xiaoling Hu, Ruyi Shi, Jie Yang, Haiyan Liu, Ting Yan, Yike Li, Enwei Xu, Yu Qian, Yanfeng Xi, Shiping Guo, Yunqing Chen, Jinfen Wang, Guodong Li, Jianfang Liang, Junmei Jia, Xing Chen, Jiansheng Guo, Tong Wang, Yanbo Zhang, Qingshan Li, Chuangui Wang, Xiaolong Cheng, Qimin Zhan and Yongping Cui _

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Oncotarget. 2016; 7:3599-3613. https://doi.org/10.18632/oncotarget.6120

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Bin Song1,2,3,*, Heyang Cui1,2,*, Yaoping Li1,4,*, Caixia Cheng1,2,5,*, Bin Yang1,4,*, Fang Wang1,2,*, Pengzhou Kong1,2,*, Hongyi Li1,2, Ling Zhang1,2, Zhiwu Jia1,2, Yanghui Bi1,2, Jiaqian Wang6, Yong Zhou6, Jing Liu1,7, Juan Wang1,2, Zhenxiang Zhao1,2, Yanyan Zhang1,7, Xiaoling Hu1,2, Ruyi Shi1,2, Jie Yang1,2, Haiyan Liu1,2,8, Ting Yan1,2, Yike Li1,7, Enwei Xu1,2,9, Yu Qian1,2, Yanfeng Xi9, Shiping Guo4, Yunqing Chen4, Jinfen Wang9, Guodong Li9, Jianfang Liang5, Junmei Jia3, Xing Chen10, Jiansheng Guo7, Tong Wang11, Yanbo Zhang11, Qingshan Li12, Chuangui Wang13, Xiaolong Cheng1,2, Qimin Zhan14 and Yongping Cui1,2

1 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China

2 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China

3 Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

4 Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China

5 Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

6 BGI-Shenzhen, Shenzhen, Guangdong, China

7 Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

8 Department of Nuclear medicine, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

9 Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China

10 Department of Endoscopy, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China

11 Department of Statistics, Shanxi Medical University, Taiyuan, Shanxi, China

12 School of Pharmaceutical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China

13 Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University, Shenyang, China

14 State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

* Authors share co-first authorship

Correspondence to:

Yongping Cui, email:

Qimin Zhan, email:

Keywords: esophageal cancer, significantly mutated genes, mutational exclusivity, oncogene

Received: August 05, 2015 Accepted: September 24, 2015 Published: October 29, 2015


Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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