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, Junyong Park, Hyo Song Kim, Kyu Hyun Park, Tae Soo Kim, Jong Lyul Park, Hyuncheol Chung, SunYoung Rha, Seon Youngs Kim

Research output: Contribution to journalArticle

16 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 Jan 1

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Exome
Ascites
Stomach Neoplasms
Carcinoma
Mutation
Neural Cell Adhesion Molecule L1
Biological Phenomena
Gene Ontology
Adjuvant Chemotherapy
Genes
Cause of Death
Stomach
Genome
Neoplasm Metastasis
Therapeutics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lim, Byungho ; Kim, Chan ; Kim, Jeong Hwan ; Kwon, Woo Sun ; Lee, Won Seok ; Kim, Jeong Min ; Park, Junyong ; Kim, Hyo Song ; Park, Kyu Hyun ; Kim, Tae Soo ; Park, Jong Lyul ; Chung, Hyuncheol ; Rha, SunYoung ; Kim, Seon Youngs. / Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites. In: Oncotarget. 2016 ; Vol. 7, No. 7. pp. 8055-8066.
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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.",
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Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites. / Lim, Byungho; Kim, Chan; Kim, Jeong Hwan; Kwon, Woo Sun; Lee, Won Seok; Kim, Jeong Min; Park, Junyong; Kim, Hyo Song; Park, Kyu Hyun; Kim, Tae Soo; Park, Jong Lyul; Chung, Hyuncheol; Rha, SunYoung; Kim, Seon Youngs.

In: Oncotarget, Vol. 7, No. 7, 01.01.2016, p. 8055-8066.

Research output: Contribution to journalArticle

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AU - Kim, Chan

AU - Kim, Jeong Hwan

AU - Kwon, Woo Sun

AU - Lee, Won Seok

AU - Kim, Jeong Min

AU - Park, Junyong

AU - Kim, Hyo Song

AU - Park, Kyu Hyun

AU - Kim, Tae Soo

AU - Park, Jong Lyul

AU - Chung, Hyuncheol

AU - Rha, SunYoung

AU - Kim, Seon Youngs

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AB - 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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