Early Gastric Cancer in Young, Asymptomatic Carriers of Germ-Line E-Cadherin Mutations

Huntsman, David G.; Carneiro, Fátima; Lewis, Frank R.; MacLeod, Patrick; Hayashi, Allen; Monaghan, Kristin G.; Maung, Raymond; Seruca, Raquel; Jackson, Charles E.; Caldas, Carlos

doi:10.1056/nejm200106213442504

Cited by 376 publications

(257 citation statements)

References 13 publications

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“…Barber et al [68] investigated immunoreactivity of cytokeratins (CK) 8/18 and vimentin by dual-label immunofluorescence, and their results failed to demonstrate the evidence of EMT. CK expression in both differentiated and dedifferentiated SRCCs had also been described in previous studies [64,69]. Moreover, N-cadherin, an EMT marker with increased expression in the presence of EMT [73] was not observed in intramucosal foci of SRC [52].…”

Section: Immunohistochemical Profile Of Hdgc and Its Relationship Witsupporting

confidence: 80%

“…These tiny (<0.1 to 10 mm) foci are restricted to the superficial lamina propria and composed of SRCs that are relatively small at the neck-zone level and usually enlarge towards the surface of the gastric mucosa [64].…”

Section: Prophylactic Gastrectomymentioning

confidence: 99%

“…Considering different studies which reported systematic complete mapping of total gastrectomies, there seems to be no restriction or convincingly preferred location of intramucosal SRCC in the stomach [60][61][62][64][65][66][67][68]. The foci were identified from cardia to prepyloric region and even in gastric metaplasia beyond the pylorus [48].…”

Section: Prophylactic Gastrectomymentioning

confidence: 99%

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Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

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Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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Familial clustering is seen in 10% of gastric cancer cases and approximately 1-3% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis.Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterised by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT>1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.6

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Section: Immunohistochemical Profile Of Hdgc and Its Relationship Witsupporting

confidence: 80%

Section: Prophylactic Gastrectomymentioning

confidence: 99%

Section: Prophylactic Gastrectomymentioning

confidence: 99%

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Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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“…10 -12,14 Apart from the low number of cases analyzed, a single neoplastic lesion was investigated per patient, which constitutes a clear drawback in the analysis, because HDGC is a disease with multiple and apparently unrelated tumor foci, scattered in the stomach of mutation carriers. 15,16 Data from 27 tumors arising in 27 patients from the 13 HDGC families studied so far still indicate CDH1 promoter hypermethylation as the most common 2nd-hit mechanism of inactivation. 10,11,14 In contrast with studies on the 2nd-hit inactivation mechanism of genes causing other neoplastic syndromes, [17][18][19][20] somatic genetic alterations (mutations and loss of heterozygosity [LOH]) of CDH1 were uncommonly found.…”

mentioning

confidence: 99%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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Background & Aims:Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. Methods: Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. Results: Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P ‫؍‬ .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. Conclusion: The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

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“…Several studies have shown that even though CDH1-mutation carriers had negative biopsies before prophylactic gastrectomy, cancer foci were detected in their gastrectomy specimens. 16,17 Management (please describe)…”

Section: How Is the Cost Effectiveness Of Alternative Diagnostic Methodsmentioning

confidence: 99%

Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC)

et al. 2013

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Early Gastric Cancer in Young, Asymptomatic Carriers of Germ-Line E-Cadherin Mutations

Abstract: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.

Cited by 376 publications

References 13 publications

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

Clinical utility gene card for: Hereditary diffuse gastric cancer (HDGC)

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