E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

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.

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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.

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Clinical spectrum and pleiotropic nature of CDH1 germline mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105807 ◽

2019 ◽

Vol 56 (4) ◽

pp. 199-208 ◽

Cited By ~ 18

Author(s):

Joana Figueiredo ◽

Soraia Melo ◽

Patrícia Carneiro ◽

Ana Margarida Moreira ◽

Maria Sofia Fernandes ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Genetic Alterations ◽

Tumour Suppressor Gene ◽

Diffuse Gastric Cancer ◽

Loss Of Function ◽

Lobular Breast Cancer ◽

Cancer Syndrome ◽

Risk Of Cancer ◽

E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2021-108226 ◽

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.

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Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

International Journal of Molecular Sciences ◽

10.3390/ijms21144904 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4904

Author(s):

Laura Caggiari ◽

Mara Fornasarig ◽

Mariangela De Zorzi ◽

Renato Cannizzaro ◽

Agostino Steffan ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Susceptibility ◽

Stop Codon ◽

Case Reports ◽

Premature Stop Codon ◽

Diffuse Gastric Cancer ◽

Cancer Syndrome ◽

The Family ◽

Hereditary Gastric Cancer ◽

E Cadherin

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.

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

Current Oncology ◽

10.3747/co.27.5663 ◽

2019 ◽

Vol 27 (2) ◽

Cited By ~ 1

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.

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Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer

Cancer ◽

10.1002/cncr.25876 ◽

2011 ◽

Vol 117 (14) ◽

pp. 3112-3117 ◽

Cited By ~ 42

Author(s):

Ze Ming Xie ◽

Lai Sheng Li ◽

Claire Laquet ◽

Frédérique Penault-Llorca ◽

Nancy Uhrhammer ◽

...

Keyword(s):

Gastric Cancer ◽

Breast Carcinoma ◽

Germline Mutations ◽

Diffuse Gastric Cancer ◽

Lobular Breast Carcinoma ◽

E Cadherin

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Cancer predisposing germline mutations in patients (pts) with urothelial cancer (UC) of the renal pelvis (R-P), ureter (U) and bladder (B).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4510 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4510-4510 ◽

Cited By ~ 7

Author(s):

Maria Isabel Carlo ◽

Liying Zhang ◽

Diana Mandelker ◽

Joseph Vijai ◽

Catharine Kline Cipolla ◽

...

Keyword(s):

Gene Mutations ◽

Germline Mutations ◽

Germline Gene ◽

Repair Pathway ◽

Cancer Syndrome ◽

Full Spectrum ◽

Inherited Cancer ◽

Hereditary Component ◽

History Of ◽

Inherited Cancer Syndrome

4510 Background: Urothelial cancers (UC) are suspected to have a substantial hereditary component, but other than highly penetrant genes such as those in mismatch-repair pathway (e.g. MSH2) typically associated with R-P/U primaries, heritable gene mutations have not been systematically studied. We sought to investigate the prevalence of known cancer pre-disposing germline mutations in pts with UC originating from all sites within the urinary tract. Methods: Pts with R-P, U and B primaries, unselected for suspicion of inherited cancer syndrome, were prospectively enrolled from medical oncology and urology clinics to a germline sequencing protocol from June 2016 to January 2017. Germline gene analysis was performed in a CLIA-certified lab using a next generation sequencing (NGS) platform (MSK-IMPACT) that analyzes tumor-normal DNA pairs. The germline gene panel consisted of 76 genes associated with hereditary cancer predisposition. Results: As of January 24, 2017, 101 pts have NGS results available, with median age 63 (31-87), 76% male, 24% female. Primary sites were B (67%), R-P/U (31%), or both (3%). 73% had organ-confined disease and 27% had metastases. 8% had early onset (≤45 yrs at diagnosis), 10% had a family history of UC, 25% had documented non-UC cancers. 25 pathogenic or likely pathogenic (P-LP) mutations were identified in 22 patients. P-LP mutations were present in 29% of pts with R-P/U primaries and 18% of pts with B primaries. 12 DNA damage response gene alterations were found (4 CHEK2, 3 BRCA1, 2 BRCA2, 1 ATM, 1 BRIP1, 1 NBN) and 8 in Lynch syndrome associated genes (5 MSH2, 2 MSH6, 1 MLH1). Other mutations include 2 APC, 1 TP53, and 1 FH. Notably 3 pts had 2 alterations each ( MSH6/ APC, BRCA2/ APC, BRCA1/ CHEK2). 9/22 pts with P-LP mutations did not meet American College of Medical Genetics criteria for genetic screening. Conclusions: 22% of UC pts had a germline mutation in a cancer-associated gene. There was an unexpectedly high frequency of pts with DNA-repair pathway mutations. Active accrual is ongoing to define the full spectrum of alterations. These results have profound implications for genetic counseling and screening and further studies are warranted.

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