scholarly journals CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 391
Author(s):  
Arthavan Selvanathan ◽  
Cheng Yee Nixon ◽  
Ying Zhu ◽  
Luigi Scietti ◽  
Federico Forneris ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cleft Lip ◽  
Structural Characteristics ◽  
Molecular Data ◽  
Diffuse Gastric Cancer ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Cleft Lip Palate ◽  
Cdh1 Mutation ◽  
Mutation Distribution

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

Cleft Lip and Palate in Ectodermal Dysplasia

2020 ◽  
pp. 105566562094912
Author(s):  
Ingrid M. Ganske ◽  
Tim Irwin ◽  
Olivia Langa ◽  
Joseph Upton ◽  
Wen-Hann Tan ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Ectodermal Dysplasia ◽  
Phenotypic Expression ◽  
Velopharyngeal Insufficiency ◽  
Pathogenic Variants ◽  
Orofacial Clefting ◽  
Outcomes Measures ◽  
Cleft Lip Palate ◽  
Dentofacial Orthopedics

Objective: Ectodermal dysplasia (ED) comprises multiple syndromes that affect skin, hair, nails, and teeth, and sometimes are associated with orofacial clefting. The purpose of this study is to (1) identify the prevalence and characteristics of cleft lip and/or palate (CL/P) in patients with ED and (2) describe the management and outcomes. Design: Retrospective review from 1990 to 2019. Patients: All patients with ED treated at Boston Children's Hospital. Main Outcomes Measures: Prevalence of CL/P was calculated and clinical details recorded: phenotypic anomalies, cleft type, operative treatment, and results of repair. Results: Of 170 patients with a purported diagnosis of ED, 24 (14%) had CL/P. Anatomic categories were bilateral CL/P (67%), unilateral CL/P (8%), and cleft palate only (25%). The most common ED syndrome (37%) was ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC). Pathogenic variants in TP63 were the most frequent finding in the 11 patients who had genetic testing. Aberrations from a typical clinical course included failure of presurgical dentofacial orthopedics, dehiscence of nasolabial adhesion, and total palatal absence requiring free-flap construction. Two patients had prolonged postoperative admission for respiratory infection. High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected the predominance of bilateral complete forms. Conclusions: As in other types of syndromic CL/P, cleft phenotypic expression in ED is more severe than the general cleft population. Further studies are needed to correlate genotype and phenotype for the distinct syndromes included in the ED spectrum.

Hereditary Diffuse Gastric Cancer: Approaches to Screening, Surveillance, and Treatment

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Nastazja Dagny Pilonis ◽  
Marc Tischkowitz ◽  
Rebecca C. Fitzgerald ◽  
Massimiliano di Pietro
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Prophylactic Surgery ◽  
Future Research ◽  
Annual Review ◽  
Publication Date ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
History Of

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene ( CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer

2019 ◽  
Vol 27 (2) ◽  
Author(s):  
M. Aronson ◽  
C. Swallow ◽  
A. Govindarajan ◽  
K. Semotiuk ◽  
Z. Cohen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Detection Rate ◽  
Gene Panel ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Detection Rates ◽  
Inherited Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

Background CDH1 pathogenic variants (PV) cause the majority of inherited diffuse-gastric cancer (DGC), but have low detection rates and vary geographically. This study examines hereditary causes of DGC in patients from Ontario, Canada. Methods Eligible DGC cases at the Zane Cohen Centre (ZCC) underwent multi-gene panel or CDH1 single-site testing if they met 2015 International Gastric Cancer Linkage Consortium (IGCLC) criteria, isolated DGC <50 or family history suggestive of an inherited cancer syndrome. A secondary aim was to review all CDH1 families at the ZCC to assess cancer penetrance. Results 85 DGC patients underwent CDH1 (n=43) or multi-gene panel testing (n=42), and 15 (17.6%) PV or likely PV were identified.  CDH1 detection rate was 9.4% (n=8/85), and 11% (n=7/65) using IGCLC criteria.  No CDH1 PV identified in isolated DGC <40, but one PV identified in isolated DGC<50.  Multi-gene panel from 42 individuals identified 9 PV (21.4%) including CDH1, STK11, ATM, BRCA2, MLH1 and MSH2.  Review of 81 CDH1 carriers revealed that 10% had DGC (median age:48, range:38-59), 41% were unaffected (median age:53, range:26-89).  Three families had lobular-breast cancer (LBC) only.  Non-DGC/LBC malignancies included colorectal, gynecological, kidney/bladder, prostate, testicular and ductal breast. Conclusions Low detection rate of CDH1 in Ontario DGC patients.  No CDH1 PV found in isolated DGC <40, but identified in isolated DGC<50. Multi-gene panels are recommended for all DGC under age 50, and those meeting the IGCLC criteria, given overlapping phenotype with other hereditary conditions. HDGC phenotype is evolving with a spectrum of non-DGC/LBC cancers.

Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges

2017 ◽  
pp. 1-12 ◽  
Author(s):  
Katrina Lowstuter ◽  
Carin R. Espenschied ◽  
Duveen Sturgeon ◽  
Charité Ricker ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Medical Management ◽  
Cancer Genetics ◽  
Medical Center ◽  
Academic Medical Center ◽  
Lifetime Risk ◽  
Diffuse Gastric Cancer ◽  
Mutation Carriers ◽  
Cdh1 Mutation ◽  
Testing Criteria

Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.

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