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Oncotarget. 2016 Jan 19;7(3):3599-613. doi: 10.18632/oncotarget.6120.

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

Song B1,2,3, Cui H1,2, Li Y1,4, Cheng C1,2,5, Yang B1,4, Wang F1,2, Kong P1,2, Li H1,2, Zhang L1,2, Jia Z1,2, Bi Y1,2, Wang J6, Zhou Y6, Liu J1,7, Wang J1,2, Zhao Z1,2, Zhang Y1,7, Hu X1,2, Shi R1,2, Yang J1,2, Liu H1,2,8, Yan T1,2, Li Y1,7, Xu E1,2,9, Qian Y1,2, Xi Y9, Guo S4, Chen Y4, Wang J9, Li G9, Liang J5, Jia J3, Chen X10, Guo J7, Wang T11, Zhang Y11, Li Q12, Wang C13, Cheng X1,2, Zhan Q14, Cui Y1,2.

Author information

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.

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.

KEYWORDS:

esophageal cancer; mutational exclusivity; oncogene; significantly mutated genes

PMID:
26528858
PMCID:
PMC4823130
DOI:
10.18632/oncotarget.6120
[Indexed for MEDLINE]
Free PMC Article

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