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.

Rho‐kinase Gene Polymorphisms in Related Disease States

“…Thus, no evidence was found to suggest that these polymorphisms play a signiicant role in lung cancer susceptibility [11]. Recently, a nonsense mutation (G285*) in ROCK1 that introduces a premature stop codon at amino acid 285, and a ROCK2 mutation (S457N) has been identiied in gastric cancer patients with peritoneal carcinomatosis [12]. Collectively, these results may suggest the importance of the ROCK gene in breast, lung, and gastric carcinomas.…”

“…Breast cancer Y405*, S1126* [10] Lung cancer P1193S [10] rs11874761, rs8085504, rs2127958, rs17202375, rs288980 [11] Gastric cancer G285* [12] Colorectal cancer rs73963110, rs35996865 [13] rs35768389, rs73963110, rs2127958, rs288980 [14] rs35996865 (in male patients) [14] V1309* [43] Clear cell renal cell carcinoma rs35996865 [16] rs8089974, rs11874761 [16] Tetralogy of Fallot rs288979, rs56085230 (Tyr269Tyr) [27] rs2292296 (Leu1097Phe), rs7237677, rs7227454, rs288989, rs45449301 (Ile432Val), rs288979, rs17202368, rs17202375, rs2271255 (Lys222Glu), rs1481280, rs8085504, rs398528, rs112165707 (Ser595Ser), rs45562542 (Thr773Ser) [27] Disease…”

“…[35] rs73963110 [35] Schizophrenia rs8085654, rs288980, rs1481280 [42] Breast cancer rs2230774 (Thr431Asn) [9] rs1130757 (Arg83Lys) [9] Gastric cancer S457N [12] Colorectal cancer rs2290156, rs10178332, rs35768389, rs10929732, rs34945852…”

“…In a colorectal cancer study, the ROCK1 mutation (typically c.3921delA leading to V1309*) is also predicted to partially delete the autoinhibitory domain [43]. ROCK1 nonsense mutation (G285*) introduces a premature stop codon at the 285th amino acid of ROCK1, leading to the truncation of ∼79% of ROCK1 [12]. The lack of a Rho-binding domain by the ROCK1 mutation could impair the Rho/ROCK pathway [12].…”

“…ROCK1 nonsense mutation (G285*) introduces a premature stop codon at the 285th amino acid of ROCK1, leading to the truncation of ∼79% of ROCK1 [12]. The lack of a Rho-binding domain by the ROCK1 mutation could impair the Rho/ROCK pathway [12]. Therefore, this mutation may cause the loss-of-function of ROCK1, because most of the functional domains, including the Rho-binding domain, are truncated by the mutation.…”