Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer

Kaurah, Pardeep; MacMillan, Andrée; Boyd, Niki; Senz, Janine; Luca, Alessandro De; Chun, Nicolette M.; Suriano, Gianpaolo; Zaor, Sonya; Manen, Lori Van; Gilpin, Cathy; Nikkel, Sarah M.; Connolly-Wilson, Mary; Weissman, Scott M.; Rubinstein, Wendy S.; Sebold, Courtney; Greenstein, Robert M.; Stroop, Jennifer; Yim, Dwight; Panzini, Benoît; McKinnon, Wendy; Greenblatt, Marc S.; Wirtzfeld, Debrah; Fontaine, Dorrie K.; Coit, Daniel G.; Yoon, Sam S.; Chung, Daniel C.; Lauwers, Gregory Y.; Pizzuti, Antonio; Vaccaro, Carlos; Redal, María Ana; Oliveira, Carla; Tischkowitz, Marc; Olschwang, Sylviane; Gallinger, Steven; Lynch, Henry T.; Green, Jane; Ford, James M.; Pharoah, Paul D.P.; Fernandez, Bridget A.; Huntsman, David G.

doi:10.1001/jama.297.21.2360

Cited by 405 publications

(359 citation statements)

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“…Genetic alterations, as LOH, which seem to be acquired later in HDGC progression, could be then targeted with drugs such as EGFR and ␣5-␤1-integrinblocking antibodies or transforming growth factor-␤-R small synthetic molecules to prevent cells from migrating and metastasis from establishing. [35][36][37][38][39][40] In conclusion, our data support the previously published rate of CDH1 promoter hypermethylation as a 2nd-hit in HDGC primary tumors, and adds LOH as a key mechanism, mainly in metastatic lesions. 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.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

et al. 2009

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“…Heterozygous germline CDH1 mutations have been described in 18-40% of HDGC families [31][32][33][34][35]. The frequency of CDH1 mutations seems to be highly variable, which may be related to the variable incidence of GC across different geographic regions.…”

Section: Genetics Of Hdgcmentioning

confidence: 99%

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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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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“…Evaluations of CDH1 mutation penetrance in large families from later studies are lower (Kaurah et al. 2007), suggesting that family ascertainment for HDGC might have skewed early estimates. Penetrance is also lower in families of European ancestry (Guilford et al.…”

Section: Discussionmentioning

confidence: 99%

“…CDH1 mutations have been found in greater than 50% of families with HDGC (Kaurah et al. 2007). In families that met clinical criteria for HDGC, men carrying pathogenic CDH1 mutations were found to have a 70% cumulative risk of developing gastric cancer by age 80, while women have a 56% cumulative risk of developing gastric cancer by age 80 (Hansford et al.…”

Section: Introductionmentioning

confidence: 99%

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Huynh

Laukaitis

2016

Molec Gen & Gen Med

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BackgroundThe reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.MethodsMutation identification was performed by next‐generation sequencing. Mutations and variant status was confirmed by Sanger sequencing in 11 family members.ResultsWe present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for HDGC. The proband from the second family presents with breast cancer and carries a previously reported pathogenic CDH1 mutation, but also reports no family history of diffuse gastric cancer.ConclusionsOur study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care.

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Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer

Abstract: Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.

Cited by 405 publications

References 50 publications

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

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

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

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

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