title: Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.
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.
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
authors.forename: Byungho
authors.initials: B
authors.lastname: Lim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Kim
authors.affiliation: Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Woo Sun
authors.initials: WS
authors.lastname: Kwon
authors.affiliation: Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeong Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyo Song
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyu Hyun
authors.initials: KH
authors.lastname: Park
authors.affiliation: Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Tae Soo
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Epigenomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Park
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Song-Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.|Department of Functional Genomics, University of Science and Technology, Daejeon, Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D001201:Ascites / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary*; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor
keywords: exome sequencing; gastric cancer; malignant ascites; peritoneal carcinomatosis; somatic mutation
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