The germline CDH1 c.48 G &gt; C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

Zhang, Liying; Xiao, Alexander; Ruggeri, Jeanine; Bacares, Ruben; Somar, Joshua; Melo, Soraia; Figueiredo, Joana; Seruca, Raquel; Shah, Manish A.

doi:10.1016/j.mrfmmm.2014.10.001

Cited by 11 publications

(9 citation statements)

References 18 publications

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“…However, assessment of non-truncating sequence variants in tumor suppressor genes can be challenging when these changes are subtle and are unknown to alter function sufficiently to predispose to cancer development. Although the focus is usually placed on its effects on protein structure and function, single nucleotide substitutions within exons can also have significant impact on mRNA processing, and disrupt protein function [7, 8]. Substitution mutations and synonymous alterations should always be studied for their potentials to disrupt pre-mRNA splicing.…”

Section: Introductionmentioning

confidence: 99%

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5’ Splice Site

et al. 2016

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Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5’ splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing.

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Section: Introductionmentioning

confidence: 99%

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5’ Splice Site

et al. 2016

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“…For that purpose, cell-based graphs (networks) were created using images of DAPI-stained cells and connecting triplets of neighbouring cells. An efficient analytical pipeline for the network was then developed and validated in a well-known model of loss of cell adhesiveness 15 16 20 21 22 23 26 27 28 29 30 31 32 .…”

Section: Resultsmentioning

confidence: 99%

Quantification of topological features in cell meshes to explore E-cadherin dysfunction

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Figueiredo

Ribeiro

et al. 2016

Sci Rep

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In cancer, defective E-cadherin leads to cell detachment, migration and metastization. Further, alterations mediated by E-cadherin dysfunction affect cell topology and tissue organization. Herein, we propose a novel quantitative approach, based on microscopy images, to analyse abnormal cellular distribution patterns. We generated undirected graphs composed by sets of triangles which accurately reproduce cell positioning and structural organization within each image. Network analysis was developed by exploring triangle geometric features, namely area, edges length and formed angles, as well as their variance, when compared with the respective equilateral triangles. We generated synthetic networks, mimicking the diversity of cell-cell interaction patterns, and evaluated the applicability of the selected metrics to study topological features. Cells expressing wild-type E-cadherin and cancer-related mutants were used to validate our strategy. Specifically, A634V, R749W and P799R cancer-causing mutants present more disorganized spatial distribution when compared with wild-type cells. Moreover, P799R exhibited higher length and angle distortions and abnormal cytoskeletal organization, suggesting the formation of very dynamic and plastic cellular interactions. Hence, topological analysis of cell network diagrams is an effective tool to quantify changes in cell-cell interactions and, importantly, it can be applied to a myriad of processes, namely tissue morphogenesis and cancer.

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“…To verify the impact of the variant in vitro, we addressed protein expression and localization, and the two main functions of E-cadherin: the ability to establish cell-cell adhesion and its role as an invasion suppressor. These are well-recognized approaches to ascertain the pathogenicity of E-cadherin missense changes [7][8][9][10][11]. With these analyses, we demonstrated that the p.(T560R) change caused a decrease in protein levels and an abnormal pattern of expression in the cytoplasm (distinct from the correct plasma membrane localization), possibly due to an impairment of Nglycosylation of E-cadherin.…”

Section: Discussionmentioning

confidence: 76%

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

et al. 2018

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Germline changes in the CDH1 tumor suppressor gene predispose to diffuse gastric cancer and lobular breast cancer. In carriers of deleterious germline CDH1 variants, prophylactic gastrectomy is recommended. In case of germline missense variants, it is mandatory to assess the functional impact on E-cadherin, the protein encoded by CDH1, and to predict their clinical significance. Herein, we have identified a recurrent germline missense variant, c.1679C>G, segregating with gastric cancer in three unrelated Spanish families. Through genetic, transcriptional, in silico and in vitro studies, we demonstrate the deleterious effect of the c.1679C>G variant and its association with hereditary diffuse gastric cancer, providing relevant data to relatives and allowing an accurate genetic counseling.

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The germline CDH1 c.48 G > C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

Cited by 11 publications

References 18 publications

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5’ Splice Site

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5’ Splice Site

Quantification of topological features in cell meshes to explore E-cadherin dysfunction

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

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