Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation

Matsukuma, Karen; Mullins, Franklin M.; Dietz, Lisa; Zehnder, James L.; Ford, James M.; Chun, Nicolette M.; Schrijver, Iris

doi:10.1016/j.humpath.2010.01.022

Cited by 15 publications

(18 citation statements)

References 9 publications

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“…CDH1 is found mainly in human and animal epithelial cells and it plays an important role in the maintenance of normal epithelial cell morphology, structural integrity and polarity. CDH1 gene expression can inhibit tumor metastasis (17)(18)(19)(20)(21)40). The protein product of the CDH1 gene is reduced or absent in many tumor tissues through several possible mechanisms such as gene mutation (40), promoter hypermethylation (22)(23)(24)(25)(26)(27) and transcriptional repression (18).…”

Section: Methylation Statusmentioning

confidence: 99%

Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer

Ling

Li²,

Ge³

et al. 2011

Int J Mol Med

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Abstract. CDH1, a cell adhesion molecule, which plays a key role in maintaining the epithelial phenotype, is regarded as an invasion-suppressor gene in light of accumulating evidence from in vitro experiments and clinical observations. In an attempt to clarify the mechanism responsible for inactivation of this gene in carcinomas, we investigated the methylation status of the CDH1 gene 5'-cpG islands and its regulatory mechanism in the progression of esophageal squamous cell carcinoma. Real-time methylation-specific polymerase chain reaction (qMSP) and treatment with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza-cdR) were conducted to analyze the methylation status at the CDH1 promoter region in the human esophageal carcinoma cell lines, Ec1 and Ec9706. A total of 235 invasive esophageal squamous cell carcinomas (EScc) at stages I-IV and their corresponding normal tissue samples, were included in an immunohistochemistry study and methylation analysis of CDH1. The results demonstrate that in Ec1 and Ec9706 cells, the CDH1 promoter is methylated and treatment with 5-Aza-cdR restored CDH1 expression. Enhanced CDH1 expression decreased cell migration, invasion ability and increased adhesion ability. decreased CDH1 expression was detected in 59.6% of EScc tissues, compared with their adjacent non-neoplastic epithelia, which had a close correlation with the primary tumor status, lymph node status, distant metatasis and clinicopathologic stage. Hypermethylation at the CDH1 promoter was detected in 97.9% of 140 cases of EScc with low CDH1 expression. The methylation of CDH1 promoters (P=0.929) was closely correlated with the lack of expression of their corresponding proteins. The cox regression model for survival analysis showed that increases in CDH1 methylation had a greater impact on the prognosis than tumor clinical stage. These findings suggest that CDH1 gene silencing by promoter hypermethylation and the resultant reduction of CDH1 expression may play an important role in the progression of EScc. CDH1 methylation was a significant predictor of survival in EScc patients after surgery.

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Section: Methylation Statusmentioning

confidence: 99%

Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer

Ling

Li²,

Ge³

et al. 2011

Int J Mol Med

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“…9,10 E-cadherin is a calcium-dependent cell-cell adhesion protein that plays a role in the maintenance of cell differentiation and the normal architecture of epithelial cells, thereby functioning as a tumor suppression protein. 5,8,10,11 Mutation in the gene results in decreased gene expression and loss of function of E-cadherin. This leads to abnormal morphogenesis and architecture of epithelial tissue, loss of cellular polarity and contact inhibition, unregulated growth, and invasion of adjacent tissue.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 Approximately 50 distinct CDH1 mutations throughout the gene have been described. 2,11,13 In addition to mutations, DNA methylation of the CDH1 promoter has been observed and may completely deactivate the gene, decreasing expression of E-cadherin. 13 Another recent observation is that when E-cadherin expression is greatly decreased or absent, exon v6-containing CD44 isoforms are over-expressed.…”

Section: Discussionmentioning

confidence: 99%

“…2,8,10,11 Diffuse gastric cancer is one of two main morphological types of gastric cancer, with intestinal-type being the other. Although both are gastric cancers, they differ in many ways.…”

Section: Discussionmentioning

confidence: 99%

“…10,16 Our case had a family history of only one known diagnosed gastric cancer; whereas other reported cases had more extensive family histories with multiple family members diagnosed with gastric cancer. 8,11,23,24 This shows the importance of informing family members about positive mutation results, since a thorough, informative family history can potentially lead to faster testing, diagnosis, and treatment.…”

mentioning

confidence: 99%

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Hereditary Diffuse Gastric Cancer: A Family Diagnosis and Treatment

Onitilo

Aryal

Engel

2012

Clinical Medicine & Research

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Hereditary diffuse gastric cancer (HDGC) is a rare cancer representing approximately 2% of all gastric cancers. It is caused by CDH1 gene mutations, inherited in an autosomal dominant fashion, that affect the function of E-cadherin. Approximately 38% of HDGC families have a CDH1 gene mutation. With an estimated 75% penetrance rate, carriers are at high risk for HDGC. We describe the case of a Caucasian male of German-Russian ancestry, carrying a CDH1 gene mutation, who survived for 18 months after being diagnosed with HDGC. The results of genetic testing undergone by his family members are also reported, along with a review of the current literature. Since surveillance methods for HDGC are ineffective and unreliable, total prophylactic gastrectomy is advised for individuals with the gene mutation. Additionally, a diagnosis of HDGC should lead to genetic evaluation of family members followed by preventative measures.

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Pathophysiology of Hereditary Diffuse Gastric Cancer

Boussioutas

2015

Gastric Cancer

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Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation

Cited by 15 publications

References 9 publications

Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer

Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer

Hereditary Diffuse Gastric Cancer: A Family Diagnosis and Treatment

Pathophysiology of Hereditary Diffuse Gastric Cancer

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