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Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites

Authors
 Byungho Lim  ;  Chan Kim  ;  Jeong-Hwan Kim  ;  Woo Sun Kwon  ;  Won Seok Lee  ;  Jeong Min Kim  ;  Jun Yong Park  ;  Hyo Song Kim  ;  Kyu Hyun Park  ;  Tae Soo Kim  ;  Jong-Lyul Park  ;  Hyun Cheol Chung  ;  Sun Young Rha  ;  Seon-Young Kim 
Citation
 Oncotarget, Vol.7(7) : 8055-8066, 2016 
Journal Title
 Oncotarget 
Issue Date
2016
MeSH
Adult ; Aged ; Ascites/genetics* ; Biomarkers, Tumor/genetics* ; Case-Control Studies ; Exome/genetics* ; Female ; Follow-Up Studies ; Genome, Human* ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Male ; Middle Aged ; Mutation/genetics* ; Neoplasm Staging ; Peritoneal Neoplasms/genetics ; Peritoneal Neoplasms/secondary* ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/genetics ; Stomach Neoplasms/pathology*
Keywords
exome sequencing ; gastric cancer ; malignant ascites ; peritoneal carcinomatosis ; somatic mutation
Abstract
Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.
Files in This Item:
T201602075.pdf Download
DOI
10.18632/oncotarget.6977
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
김태수(Kim, Tae Soo)
김효송(Kim, Hyo Song) ORCID logo https://orcid.org/0000-0002-0625-9828
라선영(Rha, Sun Young) ORCID logo https://orcid.org/0000-0002-2512-4531
박규현(Park, Kyu Hyun)
박준용(Park, Jun Yong) ORCID logo https://orcid.org/0000-0001-6324-2224
정현철(Chung, Hyun Cheol) ORCID logo https://orcid.org/0000-0002-0920-9471
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/147093
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