Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06136-x
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Funding
- National Key Research and Development Plan Program [2016YFC1302702, 2016YFC1302701, 2016YFC1302703]
- Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2016-I2M-3-001]
- National Natural Science Foundation of China [81673256]
- National High-Tech Research and Development Program of China [2014AA020609]
- Specialized Research Fund for the Doctoral Program of Higher Education [20130142110017]
- National Program for Support of Top-notch Young Professionals
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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 x 10(-10)), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 x 10-9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 x 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.
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