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

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 Youngs Kim

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8055-8066
Number of pages12
JournalOncotarget
Volume7
Issue number7
DOIs
Publication statusPublished - 2016

Bibliographical note

Funding Information:
Dr. Kim's work was supported by grants from the genomics (NRF-2012M3A9D1054670 and NRF-2014M3C9A3068554) programs of the National Research Foundation of Korea, which are funded by the Ministry of Science, ICT, and Future Planning and KRIBB Research Initiative. Dr. Rha's work was supported by a grant of the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI13C2096) and the Public Welfare & Safety Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (2010-0020841).

All Science Journal Classification (ASJC) codes

  • Oncology

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