Hereditary Diffuse Gastric Cancer.

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.

Clinical Implication of CDH1 Mutations in Genetic Testing for Diffuse Gastric Cancer Patients.

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.

Managing CDH1 Cancer Risks in a Child: Complex Decision Making in a Family With Hereditary Diffuse Gastric Cancer.

Germline pathogenic variants (PVs) in CDH1 cause hereditary diffuse gastric cancer. The management of CDH1 cases with a positive family history includes total prophylactic gastrectomy or intensive surveillance. In this study, we report a 16-year-old boy with intramucosal gastric signet ring cells in the setting of a germline CDH1 PV and a family history of early-onset gastric cancer. The approach to managing both the proband and their 9-year-old sister, who also had the CDH1 PV, presented a challenge to both clinicians and the family. Herein, we present the complexities of managing gastric cancer risk when a CDH1 PV is identified in childhood in the setting of a family history of early-onset gastric cancer.

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

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.

Subtotal versus total gastrectomy for distal diffuse-type gastric cancer.

INTRODUCTION: Diffuse-type gastric carcinoma in an aggressive form of gastric cancer. Surgery is the only potentially curative treatment. It is controversial whether patients with diffuse-type gastric carcinoma should undergo total or subtotal gastrectomy when feasible. The aim of this study is to analyze the oncologic outcomes and overall survival of patients diagnosed with distal diffuse-type gastric cancer undergoing subtotal versus total gastrectomy with curative intent. METHODS: This retrospective study included all patients with histologically confirmed diffuse-type distal gastric carcinoma and clinical staging cT1-4M0, who underwent surgery with curative intent between 2011 and 2020 in a Tertiary Referral Hospital in Chile. Clinical and pathological staging was conducted using the 8th Edition of the American Joint Committee on Cancer Classification. STG group was comprised by patients who underwent subtotal gastrectomy and TG group by patients who underwent total gastrectomy. Both groups were compared in relation to sociodemographic variables, pathology reports and perioperative data which were obtained from electronic medical records. Data analysis was obtained with Stata 16.1 Statistical Software. RESULTS: One hundred and thirty patients underwent curative intent surgery. Subtotal gastrectomy with D2-lymphadenectomy was completed in 68 patients (52%). An R0 resection was achieved in all patients. Median number of resected lymph nodes, tumor size, proximal margin and depth of invasion were similar in both groups. Pathologic staging was similar between both groups, the most frequent being Stage 3(54%). After a median follow-up of 47 months [0.3-157], no difference was observed in overall survival between both groups (5-year-OS 63% in STG group versus 51% in TG group, p = 0.097). CONCLUSIONS: Oncologic and survival outcomes were similar in patients submitted to subtotal and total gastrectomy, suggesting that a subtotal gastrectomy with D2-lymphadenectomy for distal diffuse-type gastric carcinoma is not associated with a decrease in median overall survival and is an adequate surgical approach when technically feasible.

Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13-19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer.

The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.

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

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.

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

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.

Prenatal diagnosis of hereditary diffuse gastric cancer: a case report.

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.

Becoming and being a parent with an inherited predisposition to diffuse gastric cancer: A qualitative study of young adults with a CDH1 pathogenic variant.

PURPOSE: This study explored the experiences of young people with hereditary diffuse gastric cancer (HDGC), an inherited cancer predisposition syndrome, as they navigate becoming and being a parent. DESIGN: We used interpretive description and conducted semi-structured interviews with 13 young Australians (18-39 years) with a CDH1 pathogenic variant (PV). Data were analyzed using team-based, reflexive thematic analysis. FINDINGS: Participants' reproductive decisions centered on the perceived manageability of HDGC, namely via gastrectomy, and timing of their genetic testing. Participants yet to have children and those with challenging gastrectomy experiences favored using reproductive technologies to prevent passing on their PV. Parents who had children before genetic testing described complicated decisions about having more children. Gastrectomy was considered a parental responsibility but recovery diminished parenting abilities. CONCLUSION: Young people with HDGC face unique challenges navigating reproductive decision-making and parenting with gastrectomy. Findings lend credence to calls for longitudinal, developmentally sensitive genetic counseling services.

Low expression of E-Cadherin and CDH1 variants associated with diffuse gastric cancer.

Background: Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene. Objectives: The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC. Methods: We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software. Results: We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database. Conclusions: In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

BACKGROUND: Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC). METHODS: Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed. RESULTS: Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy. CONCLUSIONS: PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

International Delphi consensus guidelines for follow-up after prophylactic total gastrectomy: the Life after Prophylactic Total Gastrectomy (LAP-TG) study.

BACKGROUND: Prophylactic total gastrectomy (PTG) remains the only means of preventing gastric cancer for people with genetic mutations predisposing to Hereditary Diffuse Gastric Cancer (HDGC), mainly in the CDH1 gene. The small but growing cohort of people undergoing PTG at a young age are expected to have a life-expectancy close to the general population, however, knowledge of the long-term effects of, and monitoring requirements after, PTG is limited. This study aims to define the standard of care for follow-up after PTG. METHODS: Through a combination of literature review and two-round Delphi consensus of major HDGC/PTG units and physicians, and patient advocates, we produced a set of recommendations for follow-up after PTG. RESULTS: There were 42 first round, and 62 second round, responses from clinicians, allied health professionals and patient advocates. The guidelines include recommendations for timing of assessments and specialties involved in providing follow-up, micronutrient supplementation and monitoring, bone health and the provision of written information. CONCLUSION: While the evidence supporting the guidelines is limited, expert consensus provides a framework to best manage people following PTG, and could support the collection of information on the long-term effects of PTG.

Integrin ß1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells.

BACKGROUND: Tumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell-cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM). METHODS: To identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA). RESULTS: Here, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin ß1 activation. Integrin ß1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin ß1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin ß1 levels. CONCLUSIONS: Integrin ß1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing.

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Young people's experiences of a CDH1 pathogenic variant: Decision-making about gastric cancer risk management.

The most effective option for gastric cancer risk management in individuals with a CDH1 germline pathogenic or likely pathogenic variant (PV) in Australia is prophylactic total gastrectomy (PTG). There is, however, increasing confidence in endoscopic surveillance as a risk management strategy thus affording individuals with a CDH1 PV with challenging decisions regarding their gastric cancer risk management. For young people, this decision-making comes at a complex development stage of emerging and young adulthood. This study aims to explore the factors that influence young people's decision-making about their gastric cancer risk management due to a CDH1 PV. Potential participants were identified and approached through the Parkville Familial Cancer Centre in Melbourne, Australia. Thematic analysis was used to interpret and analyze the data. Qualitative interviews were conducted with 13 people with a CDH1 PV aged 18 to 39 years, inclusive. The interviews found that participants' familial and shared experiences of cancer and risk management, perceived tolerance of uncertainty, and desire for control over their cancer risk were fundamental in their decision-making about their gastric cancer risk management. The participants' young adult life stage was also deemed particularly important in decisions about the timing of PTG. The findings of this study are vital to inform decisional counseling discussions with this unique population.

Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.

PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Deconvolution of diffuse gastric cancer and the suppression of CD34 on the BALB/c nude mice model.

BACKGROUND: Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene. METHODS: We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models. RESULTS: SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling. CONCLUSION: Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.