Authors: Bin Zhou, Astrid Irwanto, Yun-Miao Guo, Jin-Xin Bei, Qiao Wu, Ge Chen, Tai-Ping Zhang, Jin-Jv Lei, Qi-Sheng Feng, Li-Zhen Chen, Jianjun Liu and Yu-Pei Zhao

Bin Zhou

Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences; Beijing, China

Astrid Irwanto

Human Genetics; Genome Institute of Singapore; Agency for Science; Technology and Research, Singapore; Department of Epidemiology and Public Health; Yong Loo Lin School of Medicine; National University of Singapore; Singapore

Yun-Miao Guo

State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, China

Jin-Xin Bei

State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, China

Qiao Wu

Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences; Beijing, China

Ge Chen

Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences; Beijing, China

Tai-Ping Zhang

Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences; Beijing, China

Jin-Jv Lei

State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, China

Qi-Sheng Feng

State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, China

Li-Zhen Chen

State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, China

Jianjun Liu

Human Genetics; Genome Institute of Singapore; Agency for Science; Technology and Research, Singapore

Yu-Pei Zhao

Corresponding author: zhaoyp8028@gmail.com
Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences; Beijing, China; National Laboratory of Medical Molecular Biology; Beijing, China

Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers with more than 94% mortality rate mainly due to the widespread metastases. To find out the somatically mutated genes related to the metastasis of PDAC, we analyzed the matched tumor and normal tissue samples from a patient diagnosed with liver metastatic PDAC using intensive exome capture-sequencing analysis (> 170× coverage). Searching for the somatic mutations that drive the clonal expansion of metastasis, we identified 12 genes with higher allele frequencies (AFs) of functional mutations in the metastatic tumor, including known genes KRAS and TP53 for metastasis. Of the 10 candidate genes, 6 (ADRB1, DCLK1, KCNH2, NOP14, SIGLEC1, and ZC3H7A), together with KRAS and TP53, were clustered into a single network (p value = 1 × 10⁻²²) that is related to cancer development. Moreover, these candidate genes showed abnormal expression in PDAC tissues and functional impacts on the migration, proliferation, and colony formation abilities of pancreatic cancer cell lines. Furthermore, through digital PCR analysis, we revealed potential genomic mechanisms for the KRAS and TP53 mutations in the metastatic tumor. Taken together, our study shows the possibility for such personalized genomic profiling to provide new biological insight into the metastasis of PDAC.

Received: December 26, 2011; Accepted: May 22, 2012

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