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

Jiang Chang, Jianbo Tian, Ying Zhu, Rong Zhong, Kan Zhai, Jiaoyuan Li, Juntao Ke, QiangQiang Han, Jiao Lou, Wei Chen, Beibei Zhu, Na Shen, Yi Zhang, Yajie Gong, Yang Yang, Danyi Zou, Xiating Peng, Zhi Zhang, Xuemei Zhang, Kun Huang, Ming Yang, Li Wang, Chen Wu (), Dongxin Lin () and Xiaoping Miao ()
Additional contact information
Jiang Chang: Huazhong University of Sciences and Technology
Jianbo Tian: Huazhong University of Sciences and Technology
Ying Zhu: Huazhong University of Sciences and Technology
Rong Zhong: Huazhong University of Sciences and Technology
Kan Zhai: Chinese Academy of Medical Sciences and Peking Union Medical College
Jiaoyuan Li: Huazhong University of Sciences and Technology
Juntao Ke: Huazhong University of Sciences and Technology
QiangQiang Han: Wuhan GeneCreate Biological Engineering Co., Ltd
Jiao Lou: Huazhong University of Sciences and Technology
Wei Chen: Huazhong University of Sciences and Technology
Beibei Zhu: Huazhong University of Sciences and Technology
Na Shen: Huazhong University of Sciences and Technology
Yi Zhang: Huazhong University of Sciences and Technology
Yajie Gong: Huazhong University of Sciences and Technology
Yang Yang: Huazhong University of Sciences and Technology
Danyi Zou: Huazhong University of Sciences and Technology
Xiating Peng: Huazhong University of Sciences and Technology
Zhi Zhang: Tangshan Gongren Hospital
Xuemei Zhang: North China University of Science and Technology
Kun Huang: Huazhong University of Science and Technology
Ming Yang: Shandong Academy of Medical Sciences
Li Wang: Peking Union Medical College
Chen Wu: Chinese Academy of Medical Sciences and Peking Union Medical College
Dongxin Lin: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaoping Miao: Huazhong University of Sciences and Technology

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06136-x

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