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To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.

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In this editorial, I commented on the paper by Lin et al, published in this issue of the World Journal of Gastrointestinal Oncology. The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer (CRC). The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer (GC) stage rather than the CRC stage. Although surveillance was recommended in the conclusion, the authors did not explore this area in their study and did not include tests used for such surveillance. This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs. These include hereditary diffuse GC, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, Lynch syndrome, and three major hamartomatous polyposis syndromes associated with CRC and GC, namely Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. Careful assessment of these syndromes/conditions, including inheritance, risk of gastric and colorectal or other cancer development, genetic mutations and recommended genetic investigations, is crucial for optimum management of these patients.

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Purpose: Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression. Materials and Methods: Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing (WES) on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation and enrichment analysis were performed. Results: As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoAR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families. Conclusion: The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

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BACKGROUND: Germline mutations of E-cadherin contribute to hereditary diffuse gastric cancer (HDGC) and congenital malformations, such as oral facial clefts (OFC). However, the molecular mechanisms through which E-cadherin loss-of-function triggers distinct clinical outcomes remain unknown. We postulate that E-cadherin-mediated disorders result from abnormal interactions with the extracellular matrix and consequent aberrant intracellular signalling, affecting the coordination of cell migration. METHODS: Herein, we developed in vivo and in vitro models of E-cadherin mutants associated with either OFC or HDGC. Using a Drosophila approach, we addressed the impact of the different variants in cell morphology and migration ability. By combining gap closure migration assays and time-lapse microscopy, we further investigated the migration pattern of cells expressing OFC or HDGC variants. The adhesion profile of the variants was evaluated using high-throughput ECM arrays, whereas RNA sequencing technology was explored for identification of genes involved in aberrant cell motility. RESULTS: We have demonstrated that cells expressing OFC variants exhibit an excessive motility performance and irregular leading edges, which prevent the coordinated movement of the epithelial monolayer. Importantly, we found that OFC variants promote cell adhesion to a wider variety of extracellular matrices than HDGC variants, suggesting higher plasticity in response to different microenvironments. We unveiled a distinct transcriptomic profile in the OFC setting and pinpointed REG1A as a putative regulator of this outcome. Consistent with this, specific RNAi-mediated inhibition of REG1A shifted the migration pattern of OFC expressing cells, leading to slower wound closure with coordinated leading edges. CONCLUSIONS: We provide evidence that E-cadherin variants associated with OFC activate aberrant signalling pathways that support dynamic rearrangements of cells towards improved adaptability to the microenvironment. This proficiency results in abnormal tissue shaping and movement, possibly underlying the development of orofacial malformations.

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Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome associated with early onset diffuse gastric cancer. Definitive treatment is prophylactic total gastrectomy (PTG) associated with significant morbidity. Studies published from January 2000 to December 2022 reporting clinical, histopathological or health-related quality of life outcomes in HDGC patients undergoing PTG were identified. The study quality was assessed by the "Newcastle-Ottawa scale". Of the 257 articles screened, 21 were selected. A total of 353 patients were examined in 15 studies that reported surgical outcomes. The median age was 42 years old. The median major complication and mortality rates were 19.2% and 0.3%, respectively. The most common complications were wound infection at 4.8% followed by anastomotic leak and pulmonary complications at 4.5% each. Following PTG, 88.6% of patients had early lesions amongst 414 patients. The mean/median number of signet ring cell carcinoma foci in the gastrectomy specimens was from 2 to 78. All cases were stage 1 with no lymph node involvement. There was a wide range of psychosocial effects following PTG closely related to the physical symptoms. It is imperative for patients to receive comprehensive preoperative counselling to make an informed decision and be followed up under the care of a multidisciplinary team.

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INTRODUCTION: The objective of this study was to reclassify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing. METHODS: The relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest ClinVar definition into the following classes: benign (B), likely benign (LB), pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS). The McNemar test was used to compare the adequacy of current versus previous International GC Linkage Consortium (IGCLC) criteria. RESULTS: We reclassified a total of 247 CDH1 variants, and we identified that about 70% of B/LB variant carriers were not fulfilling the defined clinical criteria. Instead, all P/LP variants (100%) were associated with the hereditary diffuse gastric cancer (HDGC) phenotype fulfilling the 2020 ILGCC criteria, with a significant improvement (p = 0.025) compared to previous version. CONCLUSIONS: We conclude that germline CDH1 genetic testing is indicated only in families meeting the clinical criteria for the HDGC syndrome. This observation suggests that clinical phenotypes that do not clearly fulfill these criteria should not be considered for CDH1 genetic testing.

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We herein report a rare case of hereditary diffuse gastric cancer in a Japanese man. A 41-year-old man underwent esophagogastroduodenoscopy which revealed a small gastric erosion. Biopsy specimens showed signet ring cell carcinoma, and endoscopic submucosal dissection was performed. The patient's elder sister had died of gastric cancer at 38 years old. Considering the family history, a genetic test was conducted and revealed a CDH1 germline mutation. Although no carcinomatous lesion was detected endoscopically, prophylactic total gastrectomy was performed. The resection specimen showed seven microlesions of signet ring cell carcinoma confined to the lamina propria mucosae.

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The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

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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.

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Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

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BACKGROUND: Hereditary diffuse gastric cancer(HDGC) is a kind of malignant gastric cancer that is difficult to find in the early stage. However, this late onset and incomplete penetrance hereditary cancer, and its prenatal diagnosis have rarely been reported previously. CASE PRESENTATION: A 26-year-old woman was referred to genetic counseling for an ultrasonography of fetal choroid plexus cyst at 17 weeks of gestation. The ultrasonographic evaluation showed bilateral choroid plexus cysts(CPC) in the lateral ventricles, and the women showed a family history of gastric cancer and breast cancer. Trio copy number sequencing identified a pathogenic CDH1 deletion in the fetus and unaffected mother. The CDH1 deletion was found in three of the five family members tested, segregation among affected family members. The couple finally decided to terminate the pregnancy after genetic counseling by hospital geneticists due to the uncertainty of the occurrence of HDGC in the future. CONCLUSIONS: In prenatal diagnosis, a family history of cancer should be widely concerned, and prenatal diagnosis of hereditary tumors requires extensive cooperation between the prenatal diagnosis structure and the pathology department.

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BACKGROUND AND OBJECTIVE: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that increases lifetime risk of diffuse-type gastric cancer which carries a dismal overall survival. Due to the high prevalence of cancer in patients with CDH1 variants, early screening and prophylactic total gastrectomy (PTG) are recommended. This review aims to summarize the current understanding of CDH1 and HDGC, highlighting its molecular and cellular implications as well as its clinical management and research efforts. METHODS: A review of PubMed and ClinicalTrials.gov was conducted. Articles published in English and with full text were considered. PubMed was searched using the terms 'CDH1' AND 'Hereditary Diffuse Gastric Cancer'. KEY CONTENT AND FINDINGS: Loss-of-function mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified as the primary cause of HDGC. The loss of E-cadherin expression disrupts cell-cell adhesion and activates oncogenic signaling pathways, ultimately promoting cancer cell growth and dissemination. Prophylactic total gastrectomy (PTG) is recommended for pathogenic CDH1 variant carriers with a family history of diffuse gastric cancer (DGC). However, recent studies of endoscopic surveillance utilizing specific biopsy protocols have demonstrated the potential for surveillance as an alternative to total gastrectomy in selected patients. Researchers are actively investigating the consequences of E-cadherin loss in gastric epithelium and have identified potential molecular drivers of HDGC development using animal models and organoids. These discoveries provide promise for chemoprevention strategies, biomarker discovery, and targeted therapies for diffuse-type gastric cancer. CONCLUSIONS: The understanding of HDGC has significantly advanced in recent years, with the loss of E-cadherin expression identified as a crucial factor in disease pathogenesis. The use of advanced in vitro models offers substantial promise for investigating the molecular mechanisms underlying HDGC and identifying novel therapeutic targets. By leveraging advanced models, continuing clinical trials, and improving clinical management of affected individuals, researchers can work towards the development of more effective treatment strategies for HDGC. The goal is to prevent cancers from developing in patients with CDH1 gene variants and minimize the burden of cancer.

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BACKGROUND: Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance. METHODS: Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis. RESULTS: We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care. CONCLUSION: In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.

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BACKGROUND: Recognition of early signet-ring cell carcinoma (SRCC) in patients with hereditary diffuse gastric cancer (HDGC) undergoing endoscopic surveillance is challenging. We hypothesized that probe-based confocal laser endomicroscopy (pCLE) might help diagnose early cancerous lesions in the context of HDGC. The aim of this study was to identify pCLE diagnostic criteria for early SRCC. METHODS: Patients with HDGC syndrome were prospectively recruited and pCLE assessment was performed on areas suspicious for early SRCC and control regions during an endoscopic surveillance procedure. Targeted biopsies were taken for gold standard histologic assessment. In Phase I two investigators assessed video sequences off-line to identify pCLE features related to SRCC. In Phase II pCLE diagnostic criteria were evaluated in an independent video set by the investigators blinded to the histologic diagnosis. Sensitivity, specificity, accuracy, and interobserver agreement were calculated. RESULTS: Forty-two video sequences from 16 HDGC patients were included in Phase I. Four pCLE patterns associated to SRCC histologic features were identified: (A) glands with attenuated margins, (B) glands with spiculated or irregular shape, (C) heterogenous granular stroma with sparse glands, (D) enlarged vessels with tortuous shape. In Phase II, 38 video sequences from 15 patients were assessed. Criteria A and B and C had the highest diagnostic accuracy, with a κ for interobserver agreement ranging from 0.153 to 0.565. A panel comprising these 3 criteria with a cut-off of at least one positive criterion had a sensitivity of 80.9% (95%CI:58.1-94.5%) and a specificity of 70.6% (95%CI:44.0-89.7%) for a diagnosis of SRCC. CONCLUSIONS: We have generated and validated off-line pCLE criteria for early SRCC. Future real-time validation of these criteria is required.

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Gastric cancer (GC) has long been a 'Cinderella' among hereditary cancers. Until recently, single-gene testing (SGT) was the only approach to identify high-risk individuals. With the spread of multigene panel testing (MGPT), a debate arose on the involvement of other genes, particularly those pertaining to homologous recombination (HR) repair. We report our mono-institutional experience in genetic counseling and SGT for 54 GC patients, with the detection of nine pathogenic variants (PVs) (9/54:16.7%). Seven out of fifty (14%) patients who underwent SGT for unknown mutations were carriers of a PV in CDH1 (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), and MSH2 (n = 1), while one patient (2%) carried two variants of unknown significance (VUSs). CDH1 and MSH2 emerged as genes involved in early-onset diffuse and later-onset intestinal GCs, respectively. We additionally conducted MGPT on 37 patients, identifying five PVs (13.5%), including three (3/5:60%) in an HR gene (BRCA2, ATM, RAD51D) and at least one VUS in 13 patients (35.1%). Comparing PV carriers and non-carriers, we observed a statistically significant difference in PVs between patients with and without family history of GC (p-value: 0.045) or Lynch-related tumors (p-value: 0.036). Genetic counseling remains central to GC risk assessment. MGPT appeared advantageous in patients with unspecific phenotypes, although it led to challenging results.

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Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear ß-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.

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Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in 2 genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. We discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation, and its natural history. Finally, we describe current best practice for the clinical management of HDGC, including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, postoperative quality of life, and the emerging field of HDGC chemoprevention.

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Background and Aims: Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Results: Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. Conclusions: In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.

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BACKGROUND: Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. METHOD: In this study we report the clinical courses of three cases with HDGC from a single Japanese family. RESULTS: The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. CONCLUSION: It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.