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Title 

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

Authors 

Byungho LimC KimJeong Hwan KimW S KwonW S LeeJ M KimJ Y ParkH S KimK H ParkT S KimJong Lyul ParkH C ChungS Y RhaSeon-Young Kim

Publisher 

Impact Journals

Issue Date 

2016

Citation 

Oncotarget, vol. 7, no. 7, pp. 8055-8066

Keywords 

Exome sequencingGastric cancerMalignant ascitesPeritoneal carcinomatosisSomatic 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.

ISSN 

1949-2553

Link 

http://dx.doi.org/10.18632/oncotarget.6977

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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