Exome sequencing and digital PCR analyses reveal novel mutated genes related to the metastasis of pancreatic ductal adenocarcinoma.
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.
Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Bin
B
Zhou
Astrid
A
Irwanto
Yun-Miao
YM
Guo
Jin-Xin
JX
Bei
Qiao
Q
Wu
Ge
G
Chen
Tai-Ping
TP
Zhang
Jin-Jv
JJ
Lei
Qi-Sheng
QS
Feng
Li-Zhen
LZ
Chen
Jianjun
J
Liu
Yu-Pei
YP
Zhao
D000483:Alleles; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D015203:Reproducibility of Results