Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers

Cho, Soo Young; Park, Jung Won; Liu, Yang; Park, Young Soo; Kim, Ju Hee; Yang, Hanna; Um, Hyejin; Ko, Woo Ri; Lee, Byung Il; Kwon, Sun Young; Ryu, Seung Wan; Kwon, Chae Hwa; Park, Do Youn; Lee, Jae-Hyuk; Lee, Sang Il; Song, Kyu Sang; Hur, Hoon; Han, Sang‐Uk; Chang, Hee-Kyung; Kim, Sujin; Kim, Byung-Sik; Yook, Jeong-Hwan; Yoo, Moon‐Won; Kim, Beom-Su; Kim, Beom Su; Kook, Myeong–Cherl; Thiessen, Nina; He, An; Stewart, Chip; Dunford, Andrew; Kim, Jaegil; Shih, Juliann; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Steven E.; Weiner, Amaro-Taylor; Rosenberg, Mara; Getz, Gad; Yang, Eun Gyeong; Ryu, Min Hee; Bass, Adam J.; Kim, Hark Kyun

doi:10.1053/j.gastro.2017.05.012

Cited by 94 publications

(145 citation statements)

References 60 publications

(48 reference statements)

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“…In the present study, the tier 1 genetic alterations found at highest frequency ( ERBB2 , FGFR2 , PIK3CA , KRAS , BRAF , DNMT3A , MET , EGFR , PTEN , CTNNB1 , CDK6 , MDM2 , CDK4 and NRAS ) were generally consistent with the prevalence of GC alterations presented in previous studies . As recently reported, alteration in CDH1 , which encodes a calcium‐dependent cell‐to‐cell adhesion glycoprotein, was associated with poorly‐cohesive diffuse‐type histology and was a significant single‐gene prognostic marker associated with poorer survival in GC patients. Interestingly, we first found that patients with combined poorly cohesive histology and CDH1 alteration had the worst prognosis.…”

Section: Discussionsupporting

confidence: 91%

Bridging genomics and phenomics of gastric carcinoma

Cho

Ahn

Son

et al. 2019

Intl Journal of Cancer

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Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter‐relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer‐related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n = 37) and all 19 MSI‐H GCs were high TMB. High TMB was significantly more frequent in intestinal‐type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%) and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c‐MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1‐mutant GC subgroup showed the worst survival (p < 0.001). PD‐L1 expression was significantly associated with MSI‐H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.

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Section: Discussionsupporting

confidence: 91%

Bridging genomics and phenomics of gastric carcinoma

Cho

Ahn

Son

et al. 2019

Intl Journal of Cancer

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“…The process of GC cell migration includes the extension of flaky pseudopods, formation of focal adhesions, and deagglomeration of tail adhesion spots 24 . Many studies have shown that both intercellular adhesion and cytoskeleton proteins regulate cell migration by affecting the epithelial‐mesenchymal transition (EMT) 25,26 . However, our results indicated that altered expression of CD2AP did not impact the expression of EMT‐related markers such as E‐cadherin and vimentin (Figure S3).…”

Section: Resultsmentioning

confidence: 70%

“…E‐cadherin, which is involved in the formation of cell‐cell adherent junctions that define the differentiation and proliferation of epithelial cells and suppression of invasion has been identified as an important tumor suppressor in GC 32–35 . An inactivating mutation of the CDH1 gene or overexpression of its transcriptional repressor, alterations in the expression of microRNAs, deregulation of protein trafficking, and posttranslational modifications can all reduce the expression of E‐cadherin, which is closely related to the occurrence of DGC 25,26,32,36–38 …”

Section: Discussionmentioning

confidence: 99%

CD2AP inhibits metastasis in gastric cancer by promoting cellular adhesion and cytoskeleton assembly

Xie

Chen

Zheng

et al. 2020

Molecular Carcinogenesis

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Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that the alter of the cellular cytoskeleton and intercellular adhesion. CD2‐associated protein (CD2AP) is one of the critical proteins regulating cytoskeleton assembly and intercellular adhesion. However, no study has investigated the expression and biological significance of CD2AP in gastric cancer (GC) to date. Therefore, the aim of our study was to explore if the expression of CD2AP is associated with any clinical features of GC and to elucidate the underlying mechanism. Immunohistochemistry of 620 patient tissue samples indicated that the expression of CD2AP is downregulated in DGC. Moreover, a low CD2AP level was indicative of poor patient prognosis. In vitro, forced expression of CD2AP caused a significant decrease in the migration and invasion of GC cells, whereas depletion of CD2AP had the opposite effect. Immunofluorescence analysis indicated that CD2AP promoted cellular adhesion and influenced cell cytoskeleton assembly via interaction with the F‐actin capping protein CAPZA1. Overall, the upregulation of CD2AP could attenuate GC metastasis, suggesting CD2AP as a novel biomarker for the prognosis and treatment of patients with GC.

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“…The ERBB3 molecular network includes epidermal growth factor receptor (EGFR), cadherin 1 (CDH1), catenin beta 1 (CTNNB1) and EPH receptor A5 (EPHA5). These results demonstrate the importance of the ERBB network in cancer signaling, and revealed a ERBB3 network pathway model in diffuse-type GC and MSCs, and EMT.Keywords: Epithelial-mesenchymal transition; Gastric cancer; Mesenchymal stem cell; ERBB; Stem cell cancer (GC) [7]. Mutations in extracellular domains of ERBB2 are suggested to be oncogenic in lung cancer [8].…”

mentioning

confidence: 80%

“…Keywords: Epithelial-mesenchymal transition; Gastric cancer; Mesenchymal stem cell; ERBB; Stem cell cancer (GC) [7]. Mutations in extracellular domains of ERBB2 are suggested to be oncogenic in lung cancer [8].…”

Section: Introductionmentioning

confidence: 99%

Molecular Network Pathway Of ERBB In Diffuse-Type Gastric Cancer, Mesenchymal Stem Cells And Epithelial-Mesenchymal Transition

Tanabe¹

2018

J Clin Epigenet

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Epithelial-mesenchymal transition (EMT) is related to malignancy and metastasis in cancer. The molecular networks including tyrosine kinases are altered in gastric cancer (GC). This study aims to reveal the role of ERBBs (erb-b2 receptor tyrosine kinases) in EMT, and generate the molecular network pathway of ERBBs in diffusetype GC and mesenchymal stem cells (MSCs). The expression of ERBB genes was analyzed in MSCs and diffuse-type GC which has mesenchymal characteristics compared to intestinal-type GC. The signaling and molecular network of ERBB was analyzed using several databases, including cBioPortal for Cancer Genomics, Kyoto Encyclopedia of Genes and Genomes (KEGG), BioGRID and VaProS. ERBB2 and ERBB3 gene expression were up-regulated in diffuse-type GC compared to MSCs. The ERBB3 molecular network includes epidermal growth factor receptor (EGFR), cadherin 1 (CDH1), catenin beta 1 (CTNNB1) and EPH receptor A5 (EPHA5). These results demonstrate the importance of the ERBB network in cancer signaling, and revealed a ERBB3 network pathway model in diffuse-type GC and MSCs, and EMT.Keywords: Epithelial-mesenchymal transition; Gastric cancer; Mesenchymal stem cell; ERBB; Stem cell cancer (GC) [7]. Mutations in extracellular domains of ERBB2 are suggested to be oncogenic in lung cancer [8].Since previous reports have demonstrated that the ERBB members are involved in cancer and stem cell networks, it is important to elucidate the role of ERBBs in EMT and cancer resistance. To further reveal the mechanism of EMT in cancer and stem cells, we investigated the expression of ERBB genes in mesenchymal stem cells (MSCs) and diffuse-type GC, and generated ERBB network pathway model. Materials and Methods Gene expression analysis of MSCs and GCGene expression in MSCs (6 early-and 6 late-stage cultures, n=12) and diffuse-type GC (n=5) was analyzed with GeneChip® Human Genome U133 Plus 2.0 microarray (Affymetrix, Santa Clara, California, USA), as previously described [1,9,10]. Briefly, total purified cellular RNA was biotinylated and hybridized to the microarray. Cell cultureHuman MSCs from bone marrow (Lonza, Walkersville, MD, USA) were cultured in MSC growth medium (MSCGM; Lonza #PT-3001; MSC basal medium supplemented with mesenchymal cell growth supplement, L-glutamine and penicillin/streptomycin) at 37°C in a CO 2 (5%) incubator. Cells were passaged according to the manufacturer's protocol, however a slight modification was made to use trypsin-EDTA solution (Lonza #CC-3232). Lot numbers of the human MSC batches were as follows: #4F1127, #4F0312, #5F0138, #4F1560, #4F0591 and #4F0760. Informed consent was obtained for Poietics human MSC systems (Lonza) [10]. Passage numbers of MSC cultures were #4 and #22 for #4F1127, #4 and #28 for #4F0312, #4 and #24 for #5F0138, #5 and #28 for #4F1560, #4 and #28 for #4F0591, and #4 and #28 for #4F0760. Diffuse-Type GC tissuesDiffuse-type GC tissues were originally provided by the National Cancer Center Hospital after obtaining written informed consent from each patient and ...

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Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers

Cited by 94 publications

References 60 publications

Bridging genomics and phenomics of gastric carcinoma

Bridging genomics and phenomics of gastric carcinoma

CD2AP inhibits metastasis in gastric cancer by promoting cellular adhesion and cytoskeleton assembly

Molecular Network Pathway Of ERBB In Diffuse-Type Gastric Cancer, Mesenchymal Stem Cells And Epithelial-Mesenchymal Transition

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