Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer

Frébourg, Thierry; Oliveira, Carla; Hochain, P; Karam, Rachid; Manouvrier, Sylvie; Graziadio, Carla; Vekemans, Michel; Hartmann, A; Baert‐Desurmont, Stéphanie; Alexandre, Cláudio Osmar Pereira; Dumoulin, S Lejeune; Marroni, Caroline Possa; Martin, C; Castedo, Sérgio; Lovett, Michael; Winston, Julia B.; Machado, José Carlos; Attié, T; Jabs, Ethylin Wang; Cai, Juanliang; Pellerin, P; Triboulet, Jean–Pierre; Scotté, Michel; Pessot, Florence Le; Hedouin, A; Carneiro, Fátima; Blayau, Martine; Seruca, Raquel

doi:10.1136/jmg.2005.031385

Cited by 173 publications

(159 citation statements)

References 16 publications

(9 reference 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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“…Based on our pedigree structures alone, where most or all distant affected relatives used in WES had unaffected parents, some incomplete penetrance must exist, so we did not extend our calculation of sharing probabilities to include these unaffected relatives. Frebourg et al (2006) first reported two different splicing site mutations in CDH1 in two families where some relatives had CLP and diffuse gastric cancer, while other relatives had only gastric cancer. Studies of polymorphic SNPs in and near CDH1 have shown equivocal evidence of association in casecontrol studies from various populations (Letra et al 2008;Rafighdoost et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

et al. 2014

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A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders.

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“…Genes for several of these have been identified, including PVRL1 in CLP-ectodermal dysplasia syndrome (CLPED1), P63 in dominant ectrodactyly with ectodermal dysplasia and CLP (EEC) and related syndromes, and IRF6 in Van der Woude syndrome (recently reviewed in Cobourne, 2004;Cox, 2004;Marazita and Mooney, 2004). In addition, mutations in E-cadherin (CDH1) were recently found in two families with hereditary diffuse gastric cancer associated with CLP (Frebourg et al, 2005) and mutations in EFNB1 in craniofrontonasal syndrome (CFNS; Twigg et al, 2004;Wieland et al, 2004). Interestingly, PVRL1, P63, IRF6, and CDH1 are all predominantly expressed in epithelial tissues, indicating that proper epithelial differentiation, organization, or patterning play important roles in lip development.…”

Section: Other Genes and Pathwaysmentioning

confidence: 99%

Development of the upper lip: Morphogenetic and molecular mechanisms

Jiang

Bush

Lidral

2005

Developmental Dynamics

284

304

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The vertebrate upper lip forms from initially freely projecting maxillary, medial nasal, and lateral nasal prominences at the rostral and lateral boundaries of the primitive oral cavity. These facial prominences arise during early embryogenesis from ventrally migrating neural crest cells in combination with the head ectoderm and mesoderm and undergo directed growth and expansion around the nasal pits to actively fuse with each other. Initial fusion is between lateral and medial nasal processes and is followed by fusion between maxillary and medial nasal processes. Fusion between these prominences involves active epithelial filopodial and adhering interactions as well as programmed cell death. Slight defects in growth and patterning of the facial mesenchyme or epithelial fusion result in cleft lip with or without cleft palate, the most common and disfiguring craniofacial birth defect. Recent studies of craniofacial development in animal models have identified components of several major signaling pathways, including Bmp, Fgf, Shh, and Wnt signaling, that are critical for proper midfacial morphogenesis and/or lip fusion. There is also accumulating evidence that these signaling pathways cross-regulate genetically as well as crosstalk intracellularly to control cell proliferation and tissue patterning. This review will summarize the current understanding of the basic morphogenetic processes and molecular mechanisms underlying upper lip development and discuss the complex interactions of the various signaling pathways and challenges for understanding cleft lip pathogenesis.

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Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer

Cited by 173 publications

References 16 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

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

Development of the upper lip: Morphogenetic and molecular mechanisms

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