title: Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China.
abstract: 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.
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Heyang
authors.initials: H
authors.lastname: Cui
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Yaoping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Pengzhou
authors.initials: P
authors.lastname: Kong
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Li
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yanghui
authors.initials: Y
authors.lastname: Bi
authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong, China.
authors.forename: Jiaqian
authors.initials: J
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Hu
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Shi
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Nuclear medicine, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yan
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yike
authors.initials: Y
authors.lastname: Li
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.|Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Enwei
authors.initials: E
authors.lastname: Xu
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Jinfen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Endoscopy, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Statistics, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Statistics, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University, Shenyang, China.
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China.|Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D049109:Cell Proliferation / Q000187:drug effects; D002681:China; D002945:Cisplatin / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D023281:Genomics / Q000379:methods; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil
keywords: esophageal cancer; mutational exclusivity; oncogene; significantly mutated genes