Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites
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Byungho Lim1,*, Chan Kim2,3,*, Jeong-Hwan Kim4, Woo Sun Kwon3, Won Seok Lee3, Jeong Min Kim3, Jun Yong Park5, Hyo Song Kim2, Kyu Hyun Park3, Tae Soo Kim3, Jong-Lyul Park4, Hyun Cheol Chung2,3,6, Sun Young Rha2,3,6, Seon-Young Kim1,7
1Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
2Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
3Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea
4Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
5Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
6Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
7Department of Functional Genomics, University of Science and Technology, Daejeon, Korea
*These authors have contributed equally to this work
Seon-Young Kim, e-mail: [email protected]
Sun Young Rha, e-mail: [email protected]
Keywords: exome sequencing, gastric cancer, malignant ascites, peritoneal carcinomatosis, somatic mutation
Received: June 22, 2015 Accepted: January 07, 2016 Published: January 22, 2016
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.
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