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

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
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.

1066 - Phenotypic Expression of Cdh1 Germline Mutations Unselected for Hereditary Diffuse Gastric Cancer

2018 ◽  
Vol 154 (6) ◽  
pp. S-204
Author(s):  
Nicolette J. Rodriguez ◽  
Patrick Reineke ◽  
Holly LaDuca ◽  
Rosa M. Xicola ◽  
Xavier Llor
Keyword(s):  
Gastric Cancer ◽  
Phenotypic Expression ◽  
Germline Mutations ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer

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.

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

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.

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.

scholarly journals Pathology and pathobiology of the gastric carcinoma

2011 ◽  
Vol 58 (1) ◽  
pp. 39-52 ◽  
Author(s):  
Marjan Micev ◽  
Milena Cosic-Micev
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Intestinal Metaplasia ◽  
Host Susceptibility ◽  
Diffuse Gastric Cancer ◽  
Type I ◽  
Increased Risk ◽  
Spasmolytic Polypeptide ◽  
H Pylori ◽  
Risk Of Cancer

Recent epidemiological studies in Serbia revealed that gastric carcinoma is the third and the fifth main cause of cancer morbidity in men and women, respectively. Despite the declining incidence of gastric cancer, it remains the second most common cause of cancer-related deaths as it is worldwide. A well-defined carcinogenic inflammation-metaplasia-dysplasia-cancer sequence typically precedes the development of most gastric adenocarcinomas. Alterations such as gastric mucosal atrophy and intestinal metaplasia are merely markers of increased risk, while gastric epithelial dysplasia (GED) represent a direct precursor of cancer. DNA damage and increased mucosal proliferation secondary to H pylori infection, combined with a suitable host susceptibility phenotype (eg, genetic polymorphisms in interleukin IL-1B, IL-1RN, and tumor necrosis factor a TNF-a genes), are important factors in this progression pathway. However, only a small minority of patients infected with H. pylori eventually develops gastric cancer, and eradication of H pylori in these patients does not seem to eliminate the risk of cancer completely. It has been shown that atrophy may be a better indicator of risk of cancer than intestinal metaplasia, and remains to be validated in routine clinical practice according to recent proposal for new quantitative methods. It is often associated with pseudopyloric gland metaplasia in the gastric corpus mucosa, which expresses a type of trefoil peptide, the spasmolytic polypeptide (termed spasmolytic polypeptide-expressing metaplasia or SPEM) and has been shown to be linked more closely to gastric cancer than intestinal metaplasia. Better histological characterization of adenomatous (or type I), hyperplastic (foveolar or type II) and tubule-neck (mucocellular or type III) GED, two-tiered grading system (low and high grade dysplasia) as well as the introduction of Padova and Vienna international classificatons of dysplasia seem to be more helpful in GED survillance and comparative studies. A combination of histopathological features, serum markers such as pepsinogen I, and molecular tests that analyze host susceptibility polymorphisms and bacterial virulence factors, may allow development of strategies for early detection of cancer in the future. At present, pathobiology of gastric cancerogenesis is far from known, despite the progressive knowlegde on predisposing environmental conditions and genetic and epigenetic abnormalities, including tumour supressor genes, oncogenes, microsatellite instability and hypermethylation or the significance of E-cadherin mutational status association with hereditary diffuse gastric cancer syndrome. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as resection margin status and lymph node metastases and their implications have also been discussed. We aim to review these aspects, with special relevance to gastric cancer specimen reporting.

Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred

2002 ◽  
Vol 19 (5) ◽  
pp. 510-517 ◽  
Author(s):  
Carla Oliveira ◽  
Maria Cristina Bordin ◽  
Nicola Grehan ◽  
David Huntsman ◽  
Gianpaolo Suriano ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Germline Mutations ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
E Cadherin

scholarly journals Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)

2019 ◽  
Vol 56 (6) ◽  
pp. 370-379 ◽  
Author(s):  
Winifred Lo ◽  
Bin Zhu ◽  
Arvind Sabesan ◽  
Ho-Hsiang Wu ◽  
Astin Powers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Gastric Cancer ◽  
Young Age ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Germline Variants ◽  
Germline Variant ◽  
Increased Risk ◽  
E Cadherin

IntroductionHereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.MethodsOne hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).ResultsFrequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.ConclusionType and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

Sign in / Sign up

Export Citation Format

Share Document