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.

CDH1 germline mutations in healthy individuals from families with the hereditary diffuse gastric cancer syndrome

2021 ◽  
pp. jmedgenet-2021-108226
Author(s):  
Giovanni Corso ◽  
Francesca Magnoni ◽  
Giulia Massari ◽  
Cristina Maria Trovato ◽  
Alessandra Margherita De Scalzi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Healthy Subjects ◽  
Relevant Literature ◽  
Germline Mutations ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Missense Mutations ◽  
Healthy Individuals ◽  
Cancer Syndrome ◽  
The Difference

The objective of this study was to determining the frequency of different sub-types of pathogenic CDH1 germline mutations in healthy and asymptomatic individuals from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations. The collected variants were classified according to their subtype into the following classes: missense, non-sense, splicing, insertions and deletions. The χ2 test was used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was statistically significant. CDH1 genetic screening data were retrieved for 224 patients with GC and 289 healthy individuals. Among the subjects that had tested CDH1 positive, splicing mutations were found in 30.4% of the healthy individuals and in 15.2% of the patients with GC (p=0.0076). Missense mutations were also found to occur in healthy subjects with higher frequency (22.2%) than in GC-affected individuals (18.3%), but the difference was not significant in this case. In families meeting the clinical criteria for the HDGC syndrome, CDH1 splicing and missense germline mutations have been reported to occur with higher frequency in healthy subjects than in patients with cancer. This preliminary observation suggests that not all pathogenic CDH1 germline mutations confer the same risk of developing GC.

Outcomes of Surveillance Endoscopy in the Hereditary Diffuse Gastric Cancer Syndrome

2017 ◽  
Vol 152 (5) ◽  
pp. S553-S554
Author(s):  
Tomer Adar ◽  
Devanshi Patel ◽  
John T. Mullen ◽  
Gregory Y. Lauwers ◽  
Daniel C. Chung
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Surveillance Endoscopy

scholarly journals Role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

2019 ◽  
Vol 25 (23) ◽  
pp. 2878-2886 ◽  
Author(s):  
Shria Kumar ◽  
Jessica M Long ◽  
Gregory G Ginsberg ◽  
Bryson W Katona
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome

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.

scholarly journals Change of natural history of hereditary diffuse gastric cancer after identification of a novel CDH1 mutation

2017 ◽  
Vol 28 ◽  
pp. v503
Author(s):  
N. Stjepanovic ◽  
S. Castro ◽  
N. Gadea ◽  
E. Carrasco ◽  
M. Codina ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Natural History ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Mutation ◽  
History Of

scholarly journals Hereditary Diffuse Gastric Cancer: Multidisciplinary Case Report with Review of the Literature

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Rebecca Wilcox ◽  
Melody Perpich ◽  
Amy Noffsinger ◽  
Mitchell C. Posner ◽  
Kumarasen Cooper
Keyword(s):  
Gastric Cancer ◽  
Case Report ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Review Of The Literature ◽  
Cancer Syndrome ◽  
Inherited Cancer ◽  
Prophylactic Gastrectomy ◽  
Signet Ring ◽  
Inherited Cancer Syndrome

Hereditary diffuse gastric cancer (HDGC) is a rare, inherited cancer syndrome with at least one fourth of HDGC patients having an autosomal dominantly inherited mutation of CDH1 (E-Cadherin). Penetrance is relatively high (70–80% lifetime risk for gastric cancer). It is important for pathologists to recognize the syndrome's phenotype in early gastric lesions: patchy intramucosal signet ring cells often associated with pagetoid spread. Due to the insidious nature of this lesion, surveillance is limited and currently prophylactic gastrectomy is an option chosen by many HDGC patients. We present a case report from a multidisciplinary team of authors with a review of the literature that includes the updated guidelines for CDH1 genetic testing.

Screening E-Cadherin Germline Mutations in Italian Patients with Familial Diffuse Gastric Cancer: An Analysis in the District of Urbino, Region Marche, Central Italy

2003 ◽  
Vol 89 (3) ◽  
pp. 255-258 ◽  
Author(s):  
Francesco Graziano ◽  
Anna Maria Ruzzo ◽  
Italo Bearzi ◽  
Enrica Testa ◽  
Vittorio Lai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Susceptibility ◽  
Central Italy ◽  
Germline Mutations ◽  
Pedigree Analysis ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Standard Polymerase Chain Reaction ◽  
E Cadherin

Aims & Background Hereditary diffuse gastric cancer is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the E-cadherin gene (CDH1). To date, 16 truncating germline CDH1 mutations have been described in hereditary diffuse gastric cancer families in different ethnic groups, but so far, no investigation has been addressed to Italian patients. In the District of Urbino, Region Marche, Central Italy, gastric cancer is the most common tumor in men and it is the second in women after breast cancer. In this area, we investigated CDH1 mutations in patients who fulfilled the hereditary diffuse gastric cancer criteria. Material and Methods Consecutive patients with diffuse gastric cancer were considered eligible for the study. After pedigree analysis, patients who met the International Gastric Cancer Linkage Consortium criteria were studied for CDH1 mutations. After blood samples collection and DNA extraction, standard polymerase chain reaction and sequencing techniques were used for CDH1 analysis. Results In a study population of 98 patients with diffuse gastric cancer, 11 patients (11%) showed familial clustering and 3 of them met the International Gastric Cancer Linkage Consortium criteria for hereditary diffuse gastric cancer. None of the 3 patients showed inactivating germline mutation in CDH1. Conclusions According to recent studies, the frequency of CDH1 inactivating germline mutations in patients who fulfil the hereditary diffuse gastric cancer criteria may be lower than that reported in early investigations. The results of the present study in a population of Italian patients seem to confirm these data. It is likely that unidentified mutations in CDH1 or other involved genes contribute to diffuse gastric cancer susceptibility.

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