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

// Byungho Lim 1, * , Chan Kim 2, 3, * , Jeong-Hwan Kim 4 , Woo Sun Kwon 3 , Won Seok Lee 3 , Jeong Min Kim 3 , Jun Yong Park 5 , Hyo Song Kim 2 , Kyu Hyun Park 3 , Tae Soo Kim 3 , Jong-Lyul Park 4 , Hyun Cheol Chung 2, 3, 6 , Sun Young Rha 2, 3, 6 , Seon-Young Kim 1, 7 1 Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea 2 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 3 Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 4 Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea 5 Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea 6 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea 7 Department of Functional Genomics, University of Science and Technology, Daejeon, Korea * These authors have contributed equally to this work Correspondence to: Seon-Young Kim, e-mail: kimsy@kribb.re.kr Sun Young Rha, e-mail: rha7655@yuhs.ac Keywords: exome sequencing, gastric cancer, malignant ascites, peritoneal carcinomatosis, somatic mutation Received: June 22, 2015      Accepted: January 07, 2016      Published: January 22, 2016 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.