CDH1 Germline Mutations Research Articles

The first case of familial non-syndromic gastric neuroendocrine-adenocarcinoma in Iraq

Background: Gastric adenocarcinoma is the most important type of stomach cancers, and it is generally sporadic. However, about 10% of gastric adenocarcinoma occurs in familial pattern. The most important genetic causative factor in gastric adenocarcinoma is CDH1 germline mutations which cause the diffuse stomach cancer syndrome. Chen was probably the first to suggest the existence of neuroendocrine carcinoma of the stomach as a separate entity in 1988. Patients and methods: The case of the first Iraqi patient with familial mixed gastric neuroendocrine-adenocarcinoma in Iraq is described. Results: At the age of 46 years, a male patient who had strong history of gastric malignancy was diagnosed as havening stomach cancer during screening studies. His father who was himself a surgeon died at about the age of 62 years after he was operated, and found to have disseminated stomach cancer, and no surgical resection was made. The patient had two healthy younger brothers and two younger healthy sisters. A screening gastroscopy were performed also on one of his brothers and one of his sisters, and showed normal findings. The paternal grandfather died from disseminated stomach cancer, and his brother died from stomach cancer also. An initial microscopic examination of resected giant polyp on the body of the stomach showed moderately differentiated adenocarcinoma. However, further tests including serum chromogranin on resected area suggested a neuroendocrine tumor. Conclusion: Ikue Nonogaki and his research group were probably the first to report the occurrence of non-syndromic familial adenocarcinoma-neuroendocrine gastric cancer. This paper reported the occurrence of the first case of disease in Iraq which may be the fourth reported case in the world.

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.

Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

OGBN P01 Outcomes of Prophylactic Total Gastrectomy in Germline CDH1 Mutation Carriers

Abstract Background Hereditary diffuse gastric cancer (HDGC) is predominantly attributed to CDH1 [E-Cadherin] germline mutation and carries a cumulative lifetime risk of diffuse gastric cancer (DGC) of up to 70%. Definitive treatment remains prophylactic total gastrectomy (PTG) with an attendant risk of morbidity and reduced quality of life. Endoscopic surveillance following the Cambridge protocol is an alternative for selected patients, however, the impact on disease stage and long-term gastric cancer prognosis is not established. This study aims to evaluate clinical and histopathological outcomes following PTG in patients with germline CDH1 mutations with or without prior surveillance at a national HDGC referral centre. Methods Retrospective review was performed of clinicopathological outcomes for germline CDH1 mutation carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Indication for surgery of clinical stage 1 tumours was guided by patient preference, multiple visible lesions and increasing number of signet ring cell (SRC) foci. Endoscopic surveillance was offered to cases with no concerning endoscopic lesion and low number of SRC foci. Patients with confirmed DGC (≥stage 2) at diagnosis were excluded. Standard PTG procedure was open TG with D1 lymphadenectomy and preservation of posterior vagus with D2 lymphadenectomy and truncal vagotomy in selected cases. Results 48 patients underwent open PTG with D1 (93.8%) or D2 (6.2%) lymphadenectomy. PTG was deferred in 18 patients (37.5%) with median of 3 pre-operative surveillance endoscopies over 22 months (5 to 61 months). Median post-operative length of stay was 7 days (6 to 12). Major morbidity was observed in 1 case (2.1%) with no post-operative mortalities. Final stage was pT1aN0M0 in 43 patients (89.6%) and pT0N0M0 in 5 patients (10.4%). No lymph node metastases were observed and complete gastric mucosal resection was achieved for all. The 5-year estimated overall and disease-specific survival were 100% with median follow-up of 7 years. Conclusions PTG remains a robust and effective treatment for patients with pathogenic germline CDH1 mutations who are appropriate surgical candidates. There was no increase in final stage following surveillance in a dedicated specialist service and this remains a safe alternative in selected cases. For patients choosing to proceed with PTG following comprehensive pre-operative counselling, this can be undertaken with low morbidity in a specialist centre. Further long-term data are needed to determine the impact of surgery and endoscopic surveillance on survival, functional outcomes and quality of life.

Factors associated with detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations

Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC. This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices. Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P< .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P= .01), with 43% detected when≥40 samples were taken. Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

The Gastric Cancer Registry Genome Explorer: A tool for genomic discovery.

434 Background: The Gastric Cancer Registry (GCR) collects clinical questionnaire data and biospecimens from gastric cancer (GC) patients and individuals at high risk for GC (through family history of GC or a germline CDH1 mutation). Its purpose is to facilitate research into better detection and treatment strategies for GC. In 2020, the GCR Genome Explorer (GCR-GE), a publicly accessible and interactive database of clinical and genomic data, was launched to meet this goal. Methods: We generated genomic datasets from participants when GC status and archival gastric tumor tissue were available. We processed the tumor tissue (and paired normal tissue when possible) for whole genome, whole exome, and bulk RNA sequencing. The following genomic features were identified: copy number variations, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, and tumor neoantigens. We populated (1) all genomic alterations identified from GCR sequencing data, and (2) demographic and pathologic data regarding the tumor that were compiled from participant questionnaires and medical records into the GCR-GE. In addition, sequencing files from the Cancer Genome Atlas (TCGA) were similarly analyzed and uploaded as external datasets. Features of the GCR-GE include cross-study comparisons, study summaries, and queries down to the individual gene, neoantigen, and patient level. Results: In total, 243 GC patients donated tumor samples. The new GCR-GE release contains genomic datasets for 214 of these tumors, as well as datasets for 443 gastric tumors and 185 esophageal tumors from TCGA. Data generation was possible thanks to 756 subjects who enrolled in the GCR from 2011-2022. Most subjects were diagnosed with GC only (N=487), but interestingly, some met multiple criteria. For instance, 10 GC patients had a family history; 10 had a germline CDH1 mutation; and 21 patients had GC, a family history, and a germline CDH1 mutation. Efforts to upload additional datasets are ongoing. All data in the GCR-GE is downloadable. Conclusions: The GCR-GE is a comprehensive resource of genomic and clinical data. Given its accessibility, ease of use, and large cohort sizes, the GCR-GE presents a highly valuable tool for accelerating GC research.

Investigation of CDH1 germline mutations in Turkish patients with Kaposi’s sarcoma

Abstract Objectives Kaposi’s sarcoma (KS) develops from the lining cells of blood or lymphatic vessels and may appear as red, purple, brown, or black lesions. E-cadherin, CDH1, is a cell adhesion molecule located on the surface of epithelial cells. CDH1 gene expression is downregulated in several cancers and is considered a tumor suppressor gene involved in epithelial-mesenchymal transition in carcinomas. Loss of CDH1 gene expression is observed in many carcinomas, mainly diffuse gastric carcinomas and lobular breast carcinomas, as well as skin tumors. This study investigates the CDH1 germline mutations in HIV-negative (Human Immunodeficiency) Virus KS patients in the Turkish population. Methods The study examined 25 peripheral blood mononuclear cells from KS patients using the Sanger sequencing technique. Results Sixteen exons of the CDH1 gene were sequenced, and a pathogenic functional germline mutation, HET c.2245C &gt; T, p.(Arg749Trp) rs776975632, NM _004360.5, was identified in a patient with a family history of gastric and breast cancer with a high number of lesions compared to other KS patients. Discussion: KS patients with a family history of cancer could be screened for CDH1 gene and cancer-related-gen variants in the future. Conclusions KS is a rare malignancy, and genetic analysis will benefit KS patients. Further studies are needed to describe better the variations detected in a large number of KS patients in this study.

CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study.

The global distribution of germline CDH1 mutations in hereditary diffuse gastric cancer families, is highly heterogenous. The aim of this study was to determine if there is any geographic clustering of CDH1 mutations in families with the hereditary diffuse gastric cancer syndrome. Data from 1998 to 2021 were collected systematically according to the PRISMA guidelines. 571 germline CDH1 mutations were recorded worldwide, with 387 (67.8%) of them reported in 108 families. The largest clusters of CDH1 mutations were identified in central Europe, north America, northern Europe, New Zealand (Māori), and south America. A high penetrance risk for GC development was observed for c.1008G > T in New Zealand (Māori), c.1565 + 2insT in northern Europe, c.1901C > T in Portugal, and c.1003C > T in the USA. Our observations are consistent with a specific local clustering of some recurrent CDH1 mutations within specific countries.

Clinicopathological characteristics of signet-ring cell carcinoma derived from gastric fovelar epithelium.

We aimed to investigate the immunophenotype, differential diagnosis, and clinicopathological characteristics of signet-ring cell carcinoma (SRCC) derived from gastric foveolar epithelium. Clinical characteristics, endoscopic findings, histopathological features, and follow-up data of seven cases of SRCC derived from gastric foveolar epithelium with small intramucosal lesions were analyzed. Seven patients with a mean age of 38.3 years were diagnosed with SRCC derived from gastric foveolar epithelium and small intramucosal lesions, all of them were negative for CDH-1 germline mutation. The glands proliferated and expanded, and then morphologically transformed into signet-ring cells and formed clonal hyperplastic SRCC, which expanded laterally along the gastric foveolar cells to a length of 3-6 mm. Periodic acid Schiff staining was positive, while CK7 and MUC6 were negative, in all cases. Ki-67-positive cells ranged 37%-60%. During a follow-up period of 6-30 months, no patients experienced tumor recurrence or metastasis. SRCC derived from gastric foveolar epithelium is originated from the proliferative region of the bottom of the gastric pit and gland neck. It is easily missed diagnosed or misdiagnosed as it grows laterally along the gastric foveolar cells. Biological behavior, genetics, and etiology of such SRCC, as well as the clinicopathological characteristics, need to be further studied.

The Gastric Cancer Registry: A Genomic Translational Resource for Multidisciplinary Research in Gastric Cancer.

Gastric cancer is a leading cause of cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in gastric cancer, we developed the Gastric Cancer Registry (GCR), a North American repository of clinical and cancer genomics data. Participants self-enrolled online. Entry criteria into the GCR included the following: (i) diagnosis of gastric cancer, (ii) history of gastric cancer in a first- or second-degree relative, or (iii) known germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed survey. Some participants provided specimens of saliva and tumor samples. Tumor samples underwent exome sequencing, whole-genome sequencing, and transcriptome sequencing. From 2011 to 2021, 567 individuals registered and returned the clinical questionnaire. For this cohort 65% had a personal history of gastric cancer, 36% reported a family history of gastric cancer, and 14% had a germline CDH1 mutation. 89 patients with gastric cancer provided tumor samples. For the initial study, 41 tumors were sequenced using next-generation sequencing. The data was analyzed for cancer mutations, copy-number variations, gene expression, microbiome, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers' access to these datasets. The GCR is a unique, North American gastric cancer registry which integrates clinical and genomic annotation. Available for researchers through an open access, web-based explorer, the GCR Genome Explorer will accelerate collaborative gastric cancer research across the United States and world.

Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model.

Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

Molecular profiles of gastric adenocarcinoma among Hispanic patients at a safety-net healthcare system.

e16067 Background: Hispanic patients with gastric cancer are more likely to have advanced stage at diagnosis, signet ring histology, and worse survival outcomes than non-Hispanic patients. Although socioeconomic factors may contribute to these disparities, the molecular biology of gastric cancer in Hispanic patients has not been well characterized. Hispanic patients comprise &lt; 0.05% of gastric adenocarcinoma cases in The Cancer Genome Atlas (TCGA). Methods: We conducted a retrospective study of patients with gastric adenocarcinoma diagnosed between January 2019 to January 2022 at a safety net hospital in Houston, Texas. The hospital serves a patient population of which 91% are racial/ethnic minorities and 57% are Hispanic. Next generation sequencing data was obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations. We compared mutation findings in Hispanic vs non-Hispanic patients. Results: Among 56 patients with gastric adenocarcinoma, 45 (80%) were Hispanic, 11 (20%) were non-Hispanic White, Black, or other, 30 (54%) were male, median age was 54±13, and 14 (25%) were younger than 50 years old. The majority were metastatic (65%), and 6 (11%) were signet ring cell subtype. The most common pathogenic somatic variants across the entire cohort included: TP53 (55%) , CDH1 (34%) , ARID1A (25%) , LRP1B (20%) , RHOA (16%) , SMAD4 (16%) , ERBB2 (14%) , KRAS (14%) , CDKN2A (12%), and PIK3CA (12%). Microsatellite instability was found in 1 (0.02%) patient. Somatic CDH1 mutations were present in 15 (33%) Hispanic patients, of whom 7 were younger than 50 years old, and 2 (18%) non-Hispanic patients. Germline CDH1 mutations was identified in 1 Hispanic patient. TP53 mutations occurred in 14 (31%) Hispanic patients and 6 (55%) non-Hispanic patients. Conclusions: CDH1 mutations, which are associated with familial gastric cancers and more aggressive disease, were present in 33% of Hispanic patients with gastric adenocarcinoma in our study. Nearly half of these identified patients were younger than 50 years old. The high frequency of CDH1 mutations may contribute to the unique pathogenesis of gastric cancers in Hispanic patients.

Chromoendoscopy in Combination with Random Biopsies for Patients with Pathogenic CDH1 Mutations Undergoing Endoscopic Surveillance.

Germline mutations in the CDH1-gene are identified as the cause of 30-40% of cases of hereditary diffuse gastric cancer, an autosomal-dominant inherited cancer predisposition syndrome. Given this high risk of developing diffuse gastric cancer, carriers of a pathogenic CDH1 germline mutation are advised to undergo prophylactic gastrectomy. For patients preferring conservative management, endoscopic surveillance is recommended. The detection of diffuse gastric cancer using white light endoscopy, however, remains challenging. Patients with pathogenic CDH1 mutation underwent (chromo)endoscopic surveillance or endoscopy prior to surgery. Biopsies were taken at suspicious sites identified by chromoendoscopy. In addition, endoscopically normal areas were assessed with mapping biopsies. Detection rates from endoscopic biopsies (mapping vs. targeted) and gastrectomy specimen were then compared. Between 11/2015 and 12/2020, ten patients from four families with a known CDH1 germline mutation had a total of n = 24 endoscopies with n = 518 total biopsies being examined. Three patients were diagnosed with GC during the study period. These patients all had suspicious chromoendoscopic lesions (= detection rate 100%). In two of three patients who had suspicious chromoendoscopic lesions, signet cell carcinoma was also detected in mapping biopsies and multiple additional cancer foci were identified in the gastrectomy specimen. Chromoendoscopy facilitated detection of gastric carcinoma foci in CDH1 mutation carriers. Chromoendoscopy identified all patients with gastric cancer, but not all cancer foci present in these patients. We conclude that for patients opting against prophylactic total gastrectomy, the addition of chromoendoscopy to white light could be used to enhance diagnostic reliability of endoscopic surveillance.

146: THE NEED OF CDH1 GERMLINE MUTATION SCREENING IN PATIENTS WITH GASTRIC CANCER IN THE WEST

Abstract Background and aim Although the international guidelines recommend the CDH1 germline mutations screening in patients at risk of carrying pathogenic mutations, few data exist about the compliance to systematic screening programs carried out in surgical centres. Methods In the present manuscript we report the results of CDH1 germline mutations screening, undertaken in patients with gastric cancer and their relatives at high volume surgical centre of Verona University from January 2011 to July 2020. In this study HDGC 2015 Guidelines criteria were used. Results During a 10 years period, we screened 72 subjects; among them, we found a pathogenic germline genetic alteration in 37 (51,4%). 15 patients underwent to surgery due to clinically detectable tumours or positive biopsies during endoscopic surveillance; of note the youngest case of early SRC tumours detected during endoscopy was aged 15 years old. 11 underwent prophylactic gastrectomy: 8 out of 11 (72,7%) presented neoplastic foci in the specimen. During surgical operation, 7 patients required an additional oesophageal resection due to the presence of gastric mucosa at the extemporary frozen section, despite the proximal section was made above the cardia. Conclusion Based on our experience, we can conclude that the CDH1 genetic screening should be absolutely offered to high-risk Western patients, in agreement with the international guidelines. Prophylactic total gastrectomy should be considered in selected cases also under 20 years of age.

E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib.

Simple SummaryInactivating mutations in the CDH1 gene, encoding the cell adhesion protein E-cadherin, cause hereditary diffuse gastric cancer syndrome (HDGC), as well as being a hallmark of sporadic diffuse gastric cancers and lobular breast cancers. We have previously identified AKT3 as a potential vulnerability in gastric cancers lacking CDH1 expression. This study aimed to test whether drugs which inhibit the AKT3-associated gene, discoidin domain receptor tyrosine kinase 2 (DDR2) specifically targeted cells deficient in E-cadherin. We demonstrated that cells and organoids lacking E-cadherin exhibited heightened sensitivity to dasatinib, a drug that targets multiple kinases including DDR2 and SRC.The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). CDH1-deficient gastric cancers exhibit high AKT serine/threonine kinase 3 (AKT3) expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify AKT3-associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in AKT3-high gastric cancers. Of the 51 genes that were significantly correlated with AKT3 (but not AKT1), discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both Cdh1 and Tp53 mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in Cdh1-deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.

Pleiotropic cancer manifestations of germline CDH1 mutations: Risks and management.

Germline CDH1 defects are related with the development of multiple cancers due its pleiotropic nature. These several conditions are associated with various risks of penetrance and with different clinical management strategies. In this clinical review, we described the penetrance risks of gastric, breast, prostate, and colorectal cancers, in CDH1 carriers, within as well as outside the familial setting, and the best approaches to manage each risk, using either prophylactic surgery or surveillance.

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

Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited. All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software. Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter), were identified as new variants. In addition, up to 28.6% of CDH1 mutations in the 21 indicated patients were identified as c.1775G>C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rates of CDH1 in males and females were 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively. These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.

Metabolomics as a Tool for Biomarker Discovery in Gastric Cancer.

Globally, early detection and interception of gastric cancer remains limited by the lack of a broad screening paradigm for individuals with the exception of those at established hereditary risk (e.g., hereditary diffuse gastric cancer or CDH1 germline mutation status). The path forward will likely rely on establishment of biomarkers using multiple -omic approaches to detect molecular profiles associated with gastric cancer risk that can in turn be leveraged to identify individuals who may benefit from more intensive evaluation, such as screening endoscopy. In this issue, Shu and colleagues describe the results of a case-control cohort study of Asian individuals that demonstrates baseline metabolite levels are predictive of future gastric cancer risk above and beyond lifestyle and demographic risk factors. We discuss the promise and limitations of these exemplar circulating biomarkers and emphasize the need for a multifactorial risk assessment to advance precision prevention and early detection of gastric cancer.See related article by Shu et al., p. 1634.

Germline CDH1 G212E Missense Variant: Combining Clinical, In Vitro and In Vivo Strategies to Unravel Disease Burden.

Simple SummaryHereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome associated with CDH1 germline mutations. The increasing detection of CDH1 genetic variants due to multigene panel testing poses a serious clinical challenge and urges the development of effective classification strategies. In this study, we describe the identification of the novel CDH1 G212E variant in a large family strongly affected by diffuse gastric cancer. Through a comprehensive characterization pipeline, we provide evidence of the damaging nature of this genetic alteration, thus impacting patient management and family screening.E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metastasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.

Frequency of CDH1 Germline Mutations in Non-Gastric Cancers.

Simple SummaryDiffuse gastric cancer is the hallmark of the hereditary diffuse gastric cancer syndrome related with the E-cadherin germline mutations. Other cancers (non-gastric) are described in association with the CDH1 gene germline alterations. In this study, we aimed to assess the overall frequency of CDH1 mutations in non-gastric tumors reported in literature so far.Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.

CDH1 germline mutations in families with hereditary lobular breast cancer.

Pathogenic CDH1 germline mutations are associated with lobular breast cancer in the so-called hereditary lobular breast cancer (HLBC) syndrome, without apparent correlation with the classic hereditary diffuse gastric cancer (HDGC). Recent international guidelines recommend CDH1 screening also in absence of diffuse gastric cancer (DGC) history. Genomic characteristics underlying gastric and breast tumorigenesis in this varied population of patients is still unclear. In this review we revised all CDH1 germline mutations described in literature associated with lobular breast cancer (LBC). We distinguish two subgroups of CDH1 mutant carriers: (a) 'mixed' HDGC syndrome, showing both DGC plus LBC and (b) HLBC, in which DGC is absent and the LBC phenotype is predominant. A higher frequency of CDH1 mutations was identified in the HLBC syndrome with an early age at LBC diagnosis; it is possible that LBCs with CDH1 germline mutations are an independent inherited syndrome. This evidence allows us to gain biological insight into the pathophysiological mechanisms responsible for the different phenotypes of the disease and potentially tailor the prophylactic and screening procedures.