Hereditary Diffuse Gastric Cancer Research Articles

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer.

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. 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. 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. 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.

Abstract 3012: Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1

Abstract We aim to develop a new approach to systematically characterize the functional significance of “variant of uncertain significance (VUS),” focusing on the tumor suppressor gene CDH1. Genetic testing is a powerful clinical tool for identifying individuals at risk of developing inherited or familial cancers. If a potential cancer-causing genetic variant (mutation) is found, clinicians can begin managing the patient’s risk early by initiating surveillance or prophylactic treatment. For an aggressive form of inherited stomach cancer called hereditary diffuse gastric cancer (HDGC), the most commonly mutated gene is CDH1, which encodes the tumor suppressor E-Cadherin. However, due to insufficient clinical evidence, over 50% of all publicly reported CDH1 variants either have conflicting interpretations or cannot be classified, thus are not actionable. Consequently, almost 1 in 2 patients who undergo genetic testing for HDGC will not have a definitive test result and cannot benefit from early screening, causing strain on the healthcare system and psychological burden for the patients. To overcome this challenge, we developed a single-cell screening system to accurately classify CDH1 variants using a combination of functional assays, machine learning, and deep learning. Our hypothesis, now supported by preliminary data, is that pathogenic variants will disrupt normal E-Cadherin’s ability to control its signaling partner beta-catenin. Thus, loss-of-function (LoF) CDH1 variants would cause protein mislocalization and altered signaling which lead to abnormal proliferation, an early indicator for carcinogenesis. We express CDH1 variants in human cell lines and use multiplexed high-content imaging to visualize E-Cadherin and beta-catenin. Next, our deep learning pipeline extracts single-cell phenotypic profiles, and our classifier then classifies variants as functional or LoF. Initial analysis of prioritized variants show that our pipeline can accurately separate clinically pathogenic and benign variants based on their functional status as predicted by our pipeline. The outcomes of this project will contribute to a systematic approach to reclassify VUS. Citation Format: Jasmine Wen, Ajay Singh, David Nguyen, Kaitlynn Meier-Ross, Ben Martin, Vedanta Khan, Kiran Dhami, Jesse Chao. Characterizing the functional significance of "variant of uncertain significance" of the tumour suppressor CDH1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3012.

E-cadherin variants associated with oral facial clefts trigger aberrant cell motility in a REG1A-dependent manner.

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. 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. 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. 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.

A Systematic Review on Clinical and Health-Related Quality of Life Outcomes following Total Gastrectomy in Patients with Hereditary Diffuse Gastric Cancer

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.

OGBN P16 Endoscopic surveillance allows prediction of burden of early signet ring cell carcinoma in Hereditary Diffuse Gastric Cancer syndrome

Abstract Background Hereditary diffuse gastric cancer (HDGC) syndrome is commonly linked to CDH1 germline pathogenic variants (PV) and carries a high lifetime risk of diffuse gastric cancer (DGC). Definitive treatment remains prophylactic total gastrectomy (PTG). However, endoscopic surveillance can be offered to inform decision-making around surgery, although the optimal time for treatment escalation remains unclear. This study aims to establish whether histopathological assessment of endoscopic biopsies can predict burden of early signet ring cell (SRC) carcinoma on PTG specimens. Methods We performed a retrospective review of prospectively collected data on endoscopic and surgical histopathologic results from CDH1 PV carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Targeted and systematic Cambridge protocol biopsies were performed. Patients with confirmed DGC (stage 2 or higher) at baseline endoscopy were excluded. Pearson correlation was performed to assess the relationship between number of SRC foci on endoscopy and surgical specimens. Results 46 patients underwent PTG with median of 3 pre-operative surveillance endoscopies over 22 months. Final stage was pT1aN0M0 in 41 patients and pT0N0M0 in 5 patients. The number of SRC foci on PTG specimens ranged from 0 to 273. There was a strong correlation between number of SRC foci on gastrectomy specimens and from targeted and random biopsies when evaluated separately and together for last 2 and all endoscopies. The strongest correlation was seen with total number of SRC foci on random biopsies for last 2 endoscopies (r=0.738, p-value<0.001). Random biopsies outperformed targeted biopsies in prediction of early SRC burden. Conclusions Endoscopic surveillance with systematic targeted and random biopsies by expert endoscopists within a dedicated specialist service provides useful information to estimate the burden of early SRCC. Low number of SRC foci at last two endoscopies indicate scarce gastric neoplastic involvement.

The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell’s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

PATHOLOGICAL SIGNIFICANCE OF CDH1/E-CADHERIN GERMLINE SEQUENCE VARIANTS IN BREAST CANCER PATIENTS.

Germline alterations of the CDH1 (E-cadherin) tumor suppressor gene have been reported in several epithelial malignancies like hereditary diffuse gastric cancer and lobular breast cancer. E-cadherin plays a central role in proliferation, maintenance of cell-to-cell adhesion, polarity, and epithelial-mesenchymal transition of tissue cells. It is necessary to analyze the impact of the CDH1 germline sequence variants on protein and predict its clinical significance in breast cancer (BC) progression. The aim of the current study was to evaluate the impact and association of CDH1 gene potentially pathogenic variants/likely pathogenic variants (PVs/LPVs) with the initiation and progression of BC. In this study, the clinical data of 200 BC patients have been analyzed based on the type of BC, age, grade, stage, hormonal status, and risk factors. Blood samples from 50 healthy donors were used as a control. Furthermore, CDH1 gene molecular analysis, along with in silico analysis, was provided to assess the invasiveness and progression of BC caused by the E-cadherin protein. Four variants were identified by genetic screening within the CDH1 gene that included variations in exons 7, 8, 10, 11, and 13. Exon 10 had splice site mutation at position c.1337C>A, affecting the protein structure. In exon 11, there was an insertion of T base at position 1669, resulting in truncated protein compared to a normal one that can lead to the disease-causing non- sense-mediated decay and exon 13 variant c.2076T>C has already known polymorphism. In silico analysis of CDH1 showed the presence of the different variants that indicated the overall disruption of protein structure and function. The further functional analysis of these variants and their association with BC can be ensured by increasing the sample size and in vivo studies using mouse models.

Endoscopic surveillance for familial intestinal gastric cancer in low-incidence areas: An effective strategy.

While clinical practice guidelines for hereditary diffuse gastric cancer are well established, there is no consensus on the approach for familial intestinal gastric cancer (FIGC). In low-incidence gastric cancer (GC) areas such as the United States or most European countries, there are no evidence-based recommendations on endoscopic assessment in FIGC families. We aim to describe the yield of GC surveillance in these families, and to identify epidemiological risk factors for the development of GC and its precursor lesions. This is a multicenter observational study involving nine tertiary Spanish hospitals, in which all individuals fulfilling FIGC criteria who underwent endoscopic surveillance were included between 1991 and 2020. Forty-one healthy individuals of 31 families were recruited. The median number of upper gastrointestinal endoscopies per individual was 3 (interquartile range, IQR, 1-4). The median interval time between tests was 2 years (IQR 1.5-2.5), and the median follow-up was 9 years (IQR 3-14.5). In 18 (43.9%) subjects, a precursor lesion of GC was found during follow-up, and in 2 (4.9%), an early GC was identified, in which curative treatment was offered. Helicobacter pylori (Hp) infection proved to be independently associated with an increased risk of developing precursor lesions or GC, adjusted by age, gender and follow-up, with an Odds Ratio of 6.443 (1.36-30.6, P value .019). We present the first outcomes that support endoscopic surveillance with biopsies and detection of Hp in FIGC families, although the periodicity has yet to be defined.

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

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.

Laparoscopic prophylactic total gastrectomy with limited lymphadenectomy for CDH1 gene carriers.

CDH1 gene mutations are the leading etiology of hereditary diffuse gastric cancer with cumulative lifetime risk ranging up to 83%. Prophylactic total gastrectomy (PTG) is, therefore, recommended for CDH1 carriers. A laparoscopic approach may reduce operative risk versus an open operation, thus leading more patients with CDH1 mutations to pursue PTG prior to cancer development. However, more experience and oncologic outcome data are needed for a laparoscopic approach and indicated lymphadenectomy. A retrospective descriptive cohort study of adult patients with CDH1 mutations who underwent laparoscopic PTG with D1 lymphadenectomy between 2012 and 2022 was conducted at a single institution. All patients had preoperative EGD screening, and those with visible tumor lesions on surveillance EGD were excluded and not considered prophylactic. Demographics, family history, pathology, and operative course were obtained. Outcomes included complications, readmission, and postoperative weight change. Among 23 patients, median age was 48years (IQR 37, 53) and 15 (65%) were female. Family history for gastric and/or lobular breast cancer was present in 22 (96%) patients. The median [IQR] time from positive genetic testing to PTG was 347days [140, 625]. Pathologic evaluation showed five (22%) patients with foci of gastric cancer on pre-operative EGD biopsies, 10 (44%) in resected stomach specimens. All lymph nodes were negative. To address early postoperative complications, EJ anastomotic technique changed from EEA to GIA over the course of the study and feeding jejunostomy was no longer placed during PTG with minimal change in postoperative weight loss. This is the largest series, spanning 10years at a single institution, dedicated solely to a laparoscopic approach for risk-reducing PTG. A laparoscopic approach with limited lymphadenectomy resulted in acceptable surgical and oncologic outcomes. Despite no visible cancer, over half of our patients had foci of early gastric cancer. Therefore, CDH1 carriers should consider laparoscopic PTG.

Germline CDH1 variants in hereditary diffuse gastric cancer syndrome with focus on younger women.

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. 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. 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 (≤ 40years) (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). Young women carrying germline CDH1 variants with DGC arecomparatively frequent in the HDGC syndrome, and potentially at higher risk to develop DGC particularly in low-incidence areas for GC.

Prenatal diagnosis of hereditary diffuse gastric cancer: a case report

BackgroundHereditary 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 presentationA 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.ConclusionsIn 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.

Shifting perceptions on endoscopic surveillance and timing of prophylactic gastrectomy for hereditary diffuse gastric cancer.

Journal Article Shifting perceptions on endoscopic surveillance and timing of prophylactic gastrectomy for hereditary diffuse gastric cancer Get access Jolanda M van Dieren, Jolanda M van Dieren Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar Rachel S van der Post, Rachel S van der Post Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar Tanya M Bisseling Tanya M Bisseling Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands Correspondence to: Tanya M. Bisseling, Department of Gastroenterology 455, Radboud University Medical Center, PO Box 9101, Geert Grooteplein Zuid 106525 GA, Nijmegen 6500 HB, The Netherlands (e-mail: Tanya.Bisseling@radboudumc.nl) Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, znad192, https://doi.org/10.1093/bjs/znad192 Published: 24 June 2023 Article history Received: 19 May 2023 Accepted: 24 May 2023 Published: 24 June 2023

CDH1 and hereditary diffuse gastric cancer: a narrative review

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.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'.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.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.

CDH1 incidental findings in patients with personal or family history of breast cancer.

10524 Background: Pathogenic variants in CDH1 ( CDH1+) are associated with hereditary diffuse gastric cancer (HDGC), with an increased risk for DGC (~40-83%) and lobular breast cancer (BC) (~64%) [1]. The National Cancer Center Network recommends the inclusion of CDH1 in multi-gene panel testing (MGPT) for patients with significant history of BC, given its classification as a high-risk BC gene [2]. Management includes prophylactic gastrectomy or consideration of annual endoscopic biopsies and high-risk breast screening, with consideration of prophylactic mastectomy. Several studies have identified CD H1+ patients who do not meet the International Gastric Linkage Consortium’s diagnostic criteria for HDGC [3.4,5,6]. These studies have brought concerns of CDH1 pathogenic variants in patients with low risk phenotypes, given the potential for total gastrectomy to reduce DGC risk. Our study aims to investigate our cohort of patients with a personal and/or family history of BC to determine if there is a significant number of CDH1+ patients with a non-classical presentation of HDGC. Methods: 17,208 families with a history of BC who underwent MGPT were seen in a Clinical Cancer Genetics (CCG) high-risk breast clinic between August 2013 and July 2022. They were identified using a prospectively maintained MD Anderson Cancer Center CCG database. Families were categorized by their history of GC and CDH1 status. Results: Among the families, 10,202 (59%) had a proband with a personal history of BC, with a mean age of onset of 51 years. 49 families (0.28%) were CDH1+. 21 CDH1+ families (43%) had no personal and/or family history of GC. Overall, 0.12% of families within the cohort were CDH1+ and had no family history of GC. A chi-square goodness of fit test was performed comparing observed (O) versus expected frequencies (E) (O/E) of families that were: 1) CDH1+ and had a history of GC (28/28), 2) CDH1+ and no history of GC (21/21), 3) CDH1 – (benign variant or variant of unknown significance (VUS)) and a history of GC (180/164), and 4) CDH1- and no history of GC (16,979/16,995). O was determined by using a general population risk of GC (0.81%) and estimated risk of DGC for CDH1+ individuals (58.2%). The X2 was determined to be 1.576, with a p-value of 0.66483. Conclusions: In comparison to the expected frequency of incidental CDH1+ families identified via MGPT, we found that there was not a significant difference in expected and observed frequencies of families based on CDH1 status and presence of GC. These results likely reflect the incomplete penetrance and variable expressivity of HDGC, in addition to reported cases of occult signet ring cell carcinomas in biopsy samples or surgical pathology that has been reported in low risk presenting families [7]. We seek to validate these results with cohort of patients in which the diffuse gastric cancer pathology is known and to expand the analysis in patients specifically with a personal history of lobular breast cancer.

Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer

BackgroundGermline 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.MethodsWhole-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.ResultsWe 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.ConclusionIn 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.Graphical abstract

Confocal endomicroscopy diagnostic criteria for early signet-ring cell carcinoma in hereditary diffuse gastric cancer

BackgroundRecognition 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.MethodsPatients 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.ResultsForty-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.ConclusionsWe have generated and validated off-line pCLE criteria for early SRCC. Future real-time validation of these criteria is required.

Borborygmus Auscultation of Stomachless Ecologies

HDGC, or Hereditary Diffuse Gastric Cancer, is a rare form of stomach cancer caused by a mutation of the CDH1 gene. Screening protocols suggest upper endoscopy biopsies every three to six months, however, since HDGC is nearly impossible to detect in early stages, the recommended preventative measure is total gastrectomy (TG) surgery—a complete removal of the stomach. Modified lifestyles for stomachless persons include many changes, but some of the most quotidian aspects surround the novel anatomy of the intestines and their lively gastrointestinal conversations. One patient describes their own intestinal dialogue as “so loud and so rumbly that you could hear it across the room.” Another claims how their “gut has made lots of noise, but these noises [post-surgery] are new, and REALLY loud .” For these patients and others, sound and listening become key characteristics and significant aspects of a stomachless body.&#x0D; This lyric essay explores how audible bodily expressions can, on the one hand, manifest feelings of uncertainty, fear, self-loathing, and physical alienation; and, on the other hand, serve as forms of empowerment, healing, and physical remediation. Moreover, this piece is  a meditation on environmental thinking, and questions the delineations between objects of listening (sonic phenomena as material objects) and listening-subjects. Here, borborygmus auscultation foregrounds the broader ecologies (from microbiomes to conservation field sites) in which listeners are enmeshed.