RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach

Hashimoto, Taiki; Ogawa, Reiko; Tang, Tzu-Yin; Yoshida, Hiroshi; Taniguchi, Hirokazu; Katai, Hitoshi; Oda, Ichiro; Sekine, Shigeki

doi:10.1038/s41379-018-0181-9

Cited by 15 publications

(21 citation statements)

References 29 publications

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“…This nding suggests that RHOA mutation plays a potential role in the diffuse invasive pattern of GC. Second, RHOA mutation has been reported to be harbored in intramucosal CRA having a poorly differentiated component, suggesting that RHOA mutation is an early event in gastric carcinogenesis [26]. According to this nding, RHOA mutation might enhance de-differentiation of CRA into a poorly differentiated component.…”

Section: Discussionmentioning

confidence: 87%

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

Fujita

Uesugi

Sugimoto

et al. 2020

Preprint

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Background: Crawling-type adenocarcinoma (CRA) is an important gastric cancer (GC) subtype that exhibits a specific histological pattern and has characteristic clinicopathological findings. Despite its characteristic histology, little is known about the molecular characteristics of CRA. Methods: We examined 254 GC cases, including 51 cases of CRA and 126 cases having conventional differentiated adenocarcinomas (CDAs). Results for immunohistochemistry (mucin phenotype; Muc5AC, Muc6, Muc2 and CD10, CDX-2, MLH-1 and β-catenin), mutation analysis ( TP53 , KRAS and BRAF ), microsatellite instability (BAT25, BAT26, D2S123, D5S346 and D17S250), DNA methylation status by a two-panel method ( RUNX3 , MINT31 , LOX, NEUROG1 , ELMO1 and THBD ), MLH-1 promoter methylation, and allelic imbalance (AI; 1p, 3p, 4p, 5q, 8p, 9p, 13q, TP53, 18q and 22q) were examined. Results: CRAs were more likely to occur in the middle third of the stomach, in younger patients and to be macroscopically depressed. Nuclear accumulation of β-catenin and loss of MLH-1 expression were less frequent among CRA cases compared to CDA cases. At a molecular level, CRA is often characterized by the deletion mutation c.529_546 (18-base pair deletion at codon 177-182 in exon 5), in the TP53 gene (10 cases). Although the low methylation epigenotype was significantly more frequent for CRAs compared to CDAs, multiple AIs were more often seen in CRAs relative to CDAs. Conclusions: The results demonstrated that TP53 mutations, particularly c.529_546del, and multiple AIs are closely associated with CRA carcinogenesis. Our results suggest that CRA is an independent entity of GC in terms of clinicopathologic and molecular findings.

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Section: Discussionmentioning

confidence: 87%

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

Fujita

Uesugi

Sugimoto

et al. 2020

Preprint

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“…RhoA is a small GTPase that acts upon the effector of the kinase encoded by ROCK1 to regulate actin stress fibers formation. 18,21 Diseases associated with RHOA mutations include adenocarcinoma 22 and peripheral T-cell lymphoma. 23 Here, we found that RHOA and ROCK1 mRNA expression, like ACTB mRNA expression, was downregulated in SMA patients.…”

Section: Discussionmentioning

confidence: 99%

Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

Siranosian

Nery

Alves

et al. 2020

Ann Clin Transl Neurol

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Objective: Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age-and gendermatched controls (n = 34). Methods: We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes. Results: The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patientderived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation. Interpretation: Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.

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“…A recent study showed that CRA is characterized by RHOA mutation [27], which also frequently occurs in diffuse type GC [28]. The function of RhoA has been elucidated in previous studies [28][29][30]. First, RhoA is a critical regulator of actin-myosin-dependent cell contractility and cellular motility [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…The function of RhoA has been elucidated in previous studies [28][29][30]. First, RhoA is a critical regulator of actin-myosin-dependent cell contractility and cellular motility [28,29]. As a result, RHOA signaling drives amoeboid motility that may be caused by proteaseindependent cellular movement [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

et al. 2020

View full text Add to dashboard Cite

Background Crawling-type adenocarcinoma (CRA) is an important gastric cancer (GC) subtype that exhibits a specific histological pattern and has characteristic clinicopathological findings. Despite its characteristic histology, little is known about the molecular characteristics of CRA. Methods We examined 177 GC cases, including 51 cases of CRA and 126 cases having conventional differentiated adenocarcinomas (CDAs). Results for immunohistochemistry (mucin phenotype; Muc5AC, Muc6, Muc2 and CD10, CDX-2, MLH-1, p53 and β-catenin), mutation analysis (TP53, KRAS and BRAF), microsatellite instability (BAT25, BAT26, D2S123, D5S346 and D17S250), DNA methylation status by a two-panel method (RUNX3, MINT31, LOX, NEUROG1, ELMO1 and THBD), MLH-1 promoter methylation, and allelic imbalance (AI; 1p, 3p, 4p, 5q, 8p, 9p, 13q, TP53, 18q and 22q) were examined. Results CRAs were more likely to occur in the middle third of the stomach, in younger patients and to be macroscopically depressed. Nuclear accumulation of β-catenin and loss of MLH-1 expression were less frequent among CRA cases compared to CDA cases. At a molecular level, CRA is often characterized by the deletion mutation c.529_546 (18-base pair deletion at codon 177–182 in exon 5) in the TP53 gene (10 cases). Although the low methylation epigenotype was significantly more frequent for CRAs compared to CDAs, multiple AIs were more often seen in CRAs relative to CDAs. Conclusions The results demonstrated that TP53 mutations, particularly c.529_546del, and multiple AIs are closely associated with CRA carcinogenesis. Our results suggest that CRA is an independent entity of GC in terms of clinicopathologic and molecular findings.

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RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach

Cited by 15 publications

References 29 publications

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

Analysis of clinicopathological and molecular features of crawling-type gastric adenocarcinoma

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