Precursor lesions of hereditary diffuse gastric cancer (HDGC) in prophylactic gastrectomies performed in carriers of CDH1 germline mutations. The experience of a reference center

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.

Download Full-text

Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing

Annals of Oncology ◽

10.1093/annonc/mdz247.152 ◽

2019 ◽

Vol 30 ◽

pp. v316

Author(s):

I.U. Efimova ◽

E. Ignatova ◽

I. Bykov ◽

A.I. Kalinkin ◽

A.S. Tanas ◽

...

Keyword(s):

Gastric Cancer ◽

Next Generation Sequencing ◽

Germline Mutations ◽

Russian Population ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Next Generation ◽

Generation Sequencing

Download Full-text

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice

Gastric Cancer ◽

10.1007/s10120-009-0531-x ◽

2010 ◽

Vol 13 (1) ◽

pp. 1-10 ◽

Cited By ~ 98

Author(s):

Parry Guilford ◽

Bostjan Humar ◽

Vanessa Blair

Keyword(s):

Gastric Cancer ◽

Clinical Practice ◽

Germline Mutations ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer

Download Full-text

History, Pathogenesis, and Management of Familial Gastric Cancer: Original Study of John XXIII's Family

BioMed Research International ◽

10.1155/2013/385132 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Giovanni Corso ◽

Fabrizio Roncalli ◽

Daniele Marrelli ◽

Fátima Carneiro ◽

Franco Roviello

Keyword(s):

Gastric Cancer ◽

Gastric Carcinoma ◽

Germline Mutations ◽

Original Study ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Genetic Determinants ◽

Increased Risk ◽

Advanced Stages ◽

Japanese Guidelines

Background. Hereditary diffuse gastric cancer is associated with the E-cadherin germline mutations, but genetic determinants have not been identified for familial intestinal gastric carcinoma. The guidelines for hereditary diffuse gastric cancer are clearly established; however, there are no defined recommendations for the management of familial intestinal gastric carcinoma.Methods. In this study we describe Pope John XXIII's pedigree that harboured gastric cancer as well as six other family members. Family history was analysed according to the International Gastric Cancer Linkage Consortium criteria, and gastric tumours were classified in accord with the last Japanese guidelines.Results. Seven out of 109 members in this pedigree harboured gastric cancer, affecting two consecutive generations. John XXIII's clinical tumour (cTN) was classified as cT4bN3a (IV stage). In two other cases, gastric carcinomas were classified as intestinal histotype and staged as pT1bN0 and pT2N2, respectively.Conclusions. Pope John XXIII's family presents a strong aggregation for gastric cancer affecting almost seven members; it spreads through two consecutive generations. In absence of defined genetic causes and considering the increased risk of gastric cancer’s development in these families, as well as the high mortality rates and advanced stages, we propose an intensive surveillance protocol for asymptomatic members.

Download Full-text

CDH1 germline mutations in a Chinese cohort with hereditary diffuse gastric cancer

10.21203/rs.3.rs-424936/v1 ◽

2021 ◽

Author(s):

Zhiwen Pan ◽

Zhixuan Fu ◽

Cong Luo ◽

Yejiang Bao ◽

Mingli Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Germline Mutations ◽

Hereditary Diffuse Gastric Cancer ◽

Chinese Patients ◽

Diffuse Gastric Cancer ◽

Chinese Cohort ◽

Males And Females ◽

Polymerase Chain ◽

First Time ◽

Index Cases

Abstract Purpose Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited. Methods All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software. Results Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter) were identified as new variants. In addition, we found that up to 28.6% of CDH1 mutations in the 21 indicated patients identified as c.1775G > C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rate of CDH1 in males and females was 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively. Conclusion These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC, and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.

Download Full-text

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

Tumori Journal ◽

10.1177/030089160308900304 ◽

2003 ◽

Vol 89 (3) ◽

pp. 255-258 ◽

Cited By ~ 13

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.

Download Full-text