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Computerized axial tomography (CAT) scans. Baseline CT-scan (A, C, E) compared with that performed after two cycles of chemotherapy (B, D, F) shows a significant gastric, peritoneal and hepatic progression.
Source publication
Germline mutations in CDH1, the gene coding for the E-cadherin adhesion protein, are known to cause hereditary diffuse gastric cancer. We identified a new truncating germline mutation (p.Asp538Thrfs*19) in exon 11 of the CDH1 gene in a 41-year-old male with a diffuse gastric cancer. Although he had no parental history of gastric cancer, the co-segr...
Contexts in source publication
Context 1
... three cycles of treatment, a CT scan showed a clear increase of peritoneal metastases and pancreatic and hepatic involvement (Fig. 1B, D, ...
Context 2
... order to determine the extent of disease a computerized axial tomography scan (CT) and a laparoscopy were performed. Diag- nostic laparoscopy showed a below diaphragmatic peritoneal involvement while the CT scan detected a pancreatic and hepatic infiltration (Fig. 1A, C, E). The multiple biopsies performed in our Institute confirmed the previously found ...
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The use of endoscopic submucosal dissection (ESD) for treating early signet ring cell carcinoma (SRC) is controversial due to the risk of lymph node metastasis.
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Citations
... Another novel CDH1 mutation (c.1612delG), discovered by Caggiari and colleagues in 2017, also resulted in a PTC at codon 556 (p.Asp538Thrfs*19) in the extracellular fourth repeat region of a 41-year-old man with HDGC. In this case, the disease progressed rapidly to peritoneal, pancreatic, and hepatic metastasis despite 3 months of targeted therapy [9]. Both studies demonstrated that CDH1 nonsense mutations are associated with more severe clinical presentation and poor prognosis in patients with early-onset HDGC. ...
Background
Germline pathogenic variants in the cadherin-1 ( CDH1 ) gene cause a predisposition to hereditary diffuse gastric cancer (HDGC). We report an HDGC case in Vietnam and identify a novel mutation in the CDH1 gene.
Case presentation
A 28-year-old Vietnamese man was diagnosed with HDGC and a novel mutation at c.639G>A. All exons of CDH1 were sequenced in his pedigree, which revealed the c.639G>A mutation in the proband, his father, and uncle. The patient refused treatment and died 4 months after diagnosis. Endoscopic surveillance of the father and the uncle showed structural abnormalities in the father.
Conclusion
In cases of HDGC, identification of the CDH1 gene mutation is very important for better counseling and more effective strategies to prevent the development of diseases, such as prophylactic gastrectomy for family members with genetic mutations.
... All the 42 patients were found to have signet ring cell adenocarcinoma on tissue morphology. Some of the mutations studied in the patients were found to have either missense mutation or frameshift mutation, missense mutation being the commonest [18][19][20][21][22][23][24][25][26][27]. A study was conducted by Brooks-Wilson et al., which included 43 different families, 42 positive for DGC and the other one being intestinal type and in the study, CDH1 mutations were found in more than 30% of the families and 12 of those families showed familial history of multiple cases of gastric and lobular breast cancer with an autosomal dominant inheritance pattern of these mutations and almost 50% of those mutations were found to have a germline truncating CDH1 mutations [28]. ...
Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality rate, the recent rise of the diffuse form with germline E-cadherin (CDH1) mutations has added a whole new level of interest to study in detail about the association between CDH1 and diffuse gastric cancer (DGC). This introduced a set guideline formulated by Internal Gastric Cancer Linkage Consortium (IGCLC) for patients with family history of diffuse gastric cancer and invasive lobular breast cancer (ILBC). The analysis of this link was also important to set proper management protocol for patients who were CDH1 mutation carriers which now involves genetic counselling, endoscopic surveillance and screening and prophylactic total gastrectomy (PTG). The study was conducted in accordance to the 'PRISMA guidelines for reporting systematic review and meta-analysis'. Peer-reviewed studies were included from the PubMed database and relevant articles were selected to be included in the study. Appropriate inclusion/exclusion criteria with free full text English articles were applied while selecting the articles. A total of 10 studies on review with different study populations showed that of the 42 patients who were diagnosed with diffuse gastric cancer, 88% of them showed a positive germline E-cadherin gene mutation and 100% of the CDH1 mutation carriers showed microscopic changes of signet ring cell adenocarcinoma of the stomach. The beneficial effects of PTG with better survival rates and low mortality rates has outweighed other treatment modalities. Laparoscopic approach has proved to be more useful and a safer approach for gastrectomy surgeries with better post-operative management. The need for prophylactic mastectomy is also increased in the recent times and thus this requires a new set of guidelines for ILBC patients with hereditary diffuse gastric cancer (HDGC) syndrome.
... A summary of CDH1 mutations found in the promoter/5′UTR region and in all 16 exons and their surrounding sequences, are reported in Table 1, stratified on the basis of the HER2 status. Mutations resulted in: (i) missense variant in three cases (mGC-HER2 P296, mGC P310, P623); (ii) a frameshift variant in one case resulting in a truncating protein (mGC-HER2 P586) [20]; (iii) synonymous mutations in seven cases, including a new mutation (GeneBank accession number: KT820428.1) (mGC-HER2 P586, mGC P310, P295, P311, P476, P368, P490); and (iv) eight in the non-coding region (i.e., ...
... A summary of CDH1 mutations found in the promoter/5 UTR region and in all 16 exons and their surrounding sequences, are reported in Table 1, stratified on the basis of the HER2 status. Mutations resulted in: (i) missense variant in three cases (mGC-HER2 P296, mGC P310, P623); (ii) a frameshift variant in one case resulting in a truncating protein (mGC-HER2 P586) [20]; (iii) synonymous mutations in seven cases, including a new mutation (GeneBank accession number: KT820428.1) (mGC-HER2 P586, mGC P310, P295, P311, P476, P368, P490); and (iv) eight in the non-coding region (i.e., promoter/5 UTR/surrounding regions) (mGC-HER2 P586, mGC P377, P304, P294, P376, P479, P368, P490). ...
The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.
Purpose:
The objective of this study was to determine the male and female frequency of diffuse gastric cancer (DGC), the age at diagnosis, and the country of origin in a selected population with germline CDH1 variants from families with the hereditary diffuse gastric cancer (HDGC) syndrome.
Methods:
Relevant literature dating from 1998 to 2021 was systematically searched for data on CDH1 gene. The Wilcoxon rank sum test and the Chi-square test were used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was significant.
Results:
We identified 80 families fulfilling the established clinical criteria for HDGC CDH1 genetic screening. There were more women than men with DGC and germline CDH1 variant (65.5%). Stratifying the age at diagnosis, we identified an association between DGC, positive CDH1 screening and young women (≤ 40 years) (p = 0.015). The mean age at diagnosis was 39.6 ys for women and 42.5 ys for men. There was an association between CDH1 carrier status and DGC (p = 0.021).
Conclusions:
Young women carrying germline CDH1 variants with DGC are comparatively frequent in the HDGC syndrome, and potentially at higher risk to develop DGC particularly in low-incidence areas for GC.
E-cadherin (CDH1 gene) germline mutations are associated with the development of the autosomal cancer syndrome known as hereditary diffuse gastric cancer. Different patterns of CDH1 germline mutations have been described as truncating, deletion, insertion, Splice-site, non-sense, silence, and at last, missense alterations. The frequency of the different E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has been reported as extremely variable. In particular, the missense variant frequency seems to be higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. In this chapter, we described the worldwide frequency of CDH1 germline mutations in gastric cancers coming from different geographical areas.KeywordsE-cadherinGeographic distributionGastric cancer incidence
Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.
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.
Since benefits have been demonstrated in trials with perioperative chemotherapy, postoperative chemoradiotherapy, and preoperative chemoradiotherapy for patients with locally advanced gastric cancer, a second generation of randomized clinical trials evaluated some refinements of these treatment strategies. These trials included innovative combined modality programs with new drug-radiation combinations and advanced radiation therapy techniques followed by standardized gastric radical surgery to answer the several questions that emerged from the original landmark trials. The results of these trials have been recently reported and will be analyzed. Questions about patient selection and the optimal sequence and timing of treatments in the integrated approach still remain. As tumor location and histologic subtypes are associated to different aggressiveness, treatment response, and prognosis, future studies need to give more focus on gastroesophageal junction and stomach cancer as separate diseases to provide more solid data in these established tumor types. Furthermore, the new insights into histological patterns and molecular characterization of individual tumor subtype could address new and more individualized generation of combined modality treatment programs.
Gastric cancer (GC) is a complex heterogeneous disease. The better understanding of the biology and genetics of the GC had promoted the development of new subtype-specific classification with the aim to improve prognostication and precision treatments. However, although, in the last decades, a great effort to better understand tumor pathogenesis had been introduced using complex omics approaches, currently genetic-based GC categories remain still quite unsatisfactory. An exception is the two emerging scientific and clinical consensus regarding hereditary syndromes predisposing to GC, GC with microsatellite instability and HER2 gene amplification. We expect that the potential improvement allowing morphomolecular classification of GC based on the combination of clinicopathologic and molecular features could lead to a classification acceptable for a personalized prognostication and treatment of the GC in the next future. Results obtained still now are encouraging and open the way to persevere in this direction jointing morphohistopathological and molecular genetic data for a more precise classification of GC.
