Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

Higaki, Eiji; Kuwata, Takeshi; Nagatsuma, Akiko Kawano; Nishida, Yasunori; Kinoshita, Takahiro; Aizawa, Masaki; Nitta, Hiroaki; Nagino, Masato; Ochiai, Atsushi

doi:10.1007/s10120-014-0449-9

Cited by 25 publications

(22 citation statements)

References 39 publications

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“…22 The amplified EGFR is a worse factor in GC initiation, invasion and metastasis. 23 LAMC2 colocalizes with EGFR to phosphorylate EGFR and activates its downstream signaling ERK1/2. 12, 24 CD82 suppresses EGFR expression and phosphorylation in EGF- and HGF-dependent manner in Hepa1–6 cells.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer

Hou

et al. 2017

Cell Death Dis

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Drosha is an RNA III-like enzyme that has an aberrant expression in some tumors. Our previous studies showed the aberrant Drosha in gastric tumors. However, the roles of nuclear Drosha, the main regulator of microRNA (miRNA) biogenesis, in gastric cancer (GC) progression remain poorly understood. In this study, we demonstrated that nuclear Drosha is significantly associated with cell invasion of GC and that Drosha silence impedes the tumor invasion. Knockdown of Drosha led to a set of dysregulated miRNAs in GC cells. Multiple targets of these miRNAs were the members in cell migration, invasion and metastasis-associated signaling (e.g. ECM-receptor interaction, focal adhesion, p53 signaling and MAPK signaling pathway) revealed by bioinformatics analysis. LAMC2 (a key element of ECM-receptor signaling) and CD82 (a suppressor of p53 signaling) are the targets of miR-622 and miR-197, respectively. High levels of LAMC2 and low levels of CD82 were significantly related to the worse outcome for GC patients. Furthermore, overexpression of LAMC2 and knockdown of CD82 markedly promoted GC cell invasion and activated EGFR/ERK1/2-MMP7 signaling via upregulation of the expression of phosphorylated (p)-EGFR, p-ERK1/2 and MMP7. Our findings suggest that nuclear Drosha potentially has a role in the development of GC.

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Section: Discussionmentioning

confidence: 99%

Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer

Hou

et al. 2017

Cell Death Dis

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“…Another study based on 855 cases reported that gained EGFR gene copy can be found in 22.7% of GC patients, and it associates with poor disease outcome. 84 These data collectively demonstrate that EGFR CNV may be a valuable biomarker for GC.…”

Section: Chromosomementioning

confidence: 93%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

2015

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Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.

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“…In addition to NRG1 amplification, increased NRG1 GCN signals were also observed. Since there are no standardized guidelines for evaluation of NRG1 gene status, we used a cutoff value adapted from a previous study on EGFR in GC [24]; hence, NRG1 GCN gain was defined as the copy number of NRG1 per nucleus of ≥ 2.5 ( Fig. 3).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients

et al. 2017

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Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. NRG1 overexpression was observed in 141 (28.1%) GCs and significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. HER3 cytoplasmic and membranous expression were observed in 157 (31.3%) and 13 (2.6%), respectively. HER4 cytoplasmic expression was observed in 277 (55.2%), including 115 (22.9%) cases with nuclear expression. In contrast to NRG1, cytoplasmic expression of HER3 and HER4 proteins were not associated with survival, but GC patients with HER3 membranous expression showed significantly worse survival. In addition, HER4 nuclear expression was inveresely correlated with patients outcome in GC. NRG1 overexpression was also closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) cytoplasmic expression. NRG1 GCN gain (GCN ≥ 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (κ, 0.459; P < 0.001). Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040), unlike HER3 and HER4 expression. In 14 HER2positive GC with trastzumab combined chemotherapy, coexpression of NRG1 and HER3 was detected in 2 (14.3%) cases, and these GC patients group with coexpression of NRG1 and HER3 also showed a shorter PFS (P = 0.005).Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients.--

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Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

Cited by 25 publications

References 39 publications

Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer

Nuclear Drosha enhances cell invasion via an EGFR-ERK1/2-MMP7 signaling pathway induced by dysregulated miRNA-622/197 and their targets LAMC2 and CD82 in gastric cancer

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients

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