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Nat Commun. 2018 Sep 11;9(1):3688. doi: 10.1038/s41467-018-06136-x.

Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations.

Author information

1
Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China.
2
Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
3
Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China.
4
Wuhan GeneCreate Biological Engineering Co., Ltd, 430075, Wuhan, China.
5
Department of Chemotherapy and Radiotherapy, Tangshan Gongren Hospital, 063210, Tangshan, China.
6
Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, 063210, Tangshan, China.
7
Tongji School of Pharmacy, Huazhong University of Science and Technology, 430030, Wuhan, China.
8
Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 250117, Jinan, China.
9
Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 100730, Beijing, China.
10
Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. chenwu@cicams.ac.cn.
11
Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. lindx@cicams.ac.cn.
12
Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China. miaoxp@hust.edu.cn.

Abstract

Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10-10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 × 10-9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 × 10-8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.

PMID:
30206226
PMCID:
PMC6134090
DOI:
10.1038/s41467-018-06136-x
[Indexed for MEDLINE]
Free PMC Article

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