Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.

CTNNA1 codes α-1 catenin, a molecule that functions in intercellular adhesion in combination with E-cadherin (coded by CDH1). A germline pathogenic variant (GPV) of CTNNA1 increases the risk of hereditary diffuse gastric cancer (HDGC); however, this GPV has not been reported in Japan. A 35-year-old Japanese man with an advanced gastric cancer underwent comprehensive genome profiling (CGP), which led to the detection of a CTNNA1 GPV (p.Q662*). His gastric cancer tissues demonstrated a loss of α-1 catenin expression. His mother with a history of gastric signet-ring cell carcinoma had undergone genetic counseling 2 years ago, because of her broad family history of young-onset gastric cancer. Then, she had undergone germline multigene panel testing (MGPT) that included CDH1 but not CTNNA1, and no GPV had been detected. Here, Japanese precision cancer medicine revealed a GPV of a gene rarely associated with HDGC, that could not be detected by common MGPTs.

Gastric cancer (GC) commonly presents in advanced stages with metastatic spread to the peritoneal cavity, and outcomes associated with gastric cancer with peritoneal metastasis (GCPM) continue to carry a dismal prognosis. Persistent challenges in the detection of peritoneal metastasis (PM) have resulted in a relative paucity of high-quality data to inform management decisions. Several consensus groups have published recommendations to guide management, including most recently the National Comprehensive Cancer Network guidelines, which now include cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a potential treatment modality in select patients with GCPM. Multiple clinical trials have investigated the use of CRS/HIPEC and other peritoneal-directed therapies, such as intraperitoneal chemotherapy (IPC) and pressurized intraperitoneal aerosolized chemotherapy (PIPAC). As high-volume centers work to incorporate such therapies into their practice, ongoing clinical trials are aimed at understanding their efficacy. Recent findings have improved understanding of the mechanisms and pathophysiology underlying GCPM while the discovery of novel targets offers potential for drug development and therapeutic strategies to overcome treatment resistance. This review highlights recent advancements and addresses the persistent challenges in managing GCPM while also offering a comprehensive summary of current guidelines and treatment strategies.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

Whether carriers of BRCA1 or BRCA2 pathogenic variants have increased risks of childhood, adolescent, and young adult cancers is controversial. We aimed to evaluate this risk and to inform clinical care of young BRCA1 and BRCA2 pathogenic variant carriers and genetic testing for childhood, adolescent, and young adult cancer patients.

Using data from 47 117 individuals from 3086 BRCA1 or BRCA2 families, we conducted pedigree analysis to estimate relative risks (RRs) for cancers diagnosed before age 30 years.

Our data included 274 cancers diagnosed before age 30 years: 139 breast cancers, 10 ovarian cancers, and 125 nonbreast nonovarian cancers. Associations for breast cancer in young adulthood (aged 20-29 years) were found with relative risks of 11.4 (95% confidence interval [CI] = 5.5 to 23.7) and 5.2 (95% CI = 1.6 to 17.7) for BRCA1 and BRCA2 pathogenic variant carriers, respectively. No association was found for any other investigated childhood, adolescent, and young adult cancer or for all nonbreast nonovarian cancers combined; the relative risks were 0.4 (95% CI = 0.1 to 1.4) and 1.4 (95% CI = 0.7 to 3.0) in BRCA1 and BRCA2 pathogenic variant carriers, respectively.

We found no evidence that BRCA1 and BRCA2 pathogenic variant carriers have an increased childhood, adolescent, and young adult cancer risk aside from breast cancer in women aged between 20 and 30 years. Our results, along with a critical evaluation of previous germline sequencing studies, suggest that the childhood and adolescent cancer risk conferred by BRCA1 and BRCA2 pathogenic variant would be low (ie, RR < 2) if it existed. Our findings do not support pathogenic variant testing for offspring of BRCA1 and BRCA2 pathogenic variant carriers at ages younger than 18 years or for conducting BRCA1 and BRCA2 pathogenic variant testing for childhood and adolescent cancer patients.

We report the case of a 75-year-old woman with a pancreatic body mass. Pathological findings from endoscopic ultrasonography-guided fine-needle aspiration revealed medullary carcinoma of the pancreas (MCP). Deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H) were identified through immunohistochemistry and next generation sequencing, respectively. While immunohistochemistry suggested MLH1 abnormality, no MLH1 mutation was; hypermethylation of the MLH1 promoter was later confirmed via bisulfite sequencing. The patient initially received nab-paclitaxel plus gemcitabine, achieving tumor shrinkage. Upon tumor regrowth, she was treated with the anti-programmed cell death-1 immune checkpoint inhibitor (ICI) pembrolizumab, which resulted in significant tumor reduction. This is the first case report of MCP with dMMR/MSI-H due to MLH1 promoter hypermethylation, effectively treated with an ICI.

It is largely unidentified concerning the underlying genetic causes responsible for triple-negative breast cancers (TNBC), with unpredictable disease recurrence. This study aimed to examine the role of ZNF703 (Zinc finger 703) in the malignant behaviors of TNBC and its role in predicting disease-free survival (DFS).

After downregulation of ZNF703 with short interfering RNA (siRNA), we examined the proliferation of TNBC cell line MDA-MB-231 by sulforhodamine B (SRB) assay, the invasion of cells by a transwell invasion model, and the migration of cells by the monolayer wound-healing experiment. mRNA-sequencing data of ZNF703, BRCA1, BRCA2, PALB2, CHEK2, CDH1, PTEN, STK11, ATM, and TP53, and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) dataset for a total of 157 stage I-III TNBC samples. The selection of modeling features was executed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm to avoid model overfitting. The TIMER 2.0 algorithm determined the associations between immune score and gene expressions. Kaplan-Meier analysis was conducted to plot survival analyses.

The aggressive tumor morphology, cell proliferation, cell migration, and cell invasion were partly reversed by the siRNA knockdown of ZNF703 in MDA-MB-231 cells. ZNF703 knockdown markedly enhanced the killing ability of cisplatin These phenomena were verified by another TNBC cell line BT-549. Patients with high expression of ZNF703 had an inferior DFS for TNBC patients at 8 years [Hazard ratio (HR) for high expression vs. low expression was 2.71; 95 %CI, 1.03 to 7.14, P = 0.044]. Receiver Operating Characteristic (ROC) curve was also developed, indicating the area under the curve (AUC) was 0.744 (95 %CI, 0.628 to 0.861) at 5 years and 0.738 (95 %CI, 0.552 to 0.924) at 8 years, respectively. In addition, LASSO regression results showed that the optimal penalization parameter corresponds to two prognostic genes - ZNF703 and STK11. The risk score was computed as Risk Score (RS) = 0.1033*ZNF703 + 0.2131*STK11 (named "ZS -TNBC model"). The high expression of both ZNF703 and STK11 had as high as 7.035 HR in comparison to the low-expression category (95 %CI, 2.044 to 24.206, P = 0.00197).

ZNF703 is required for the growth, invasion, and migratory behavior of TNBC cells. Downregulation of ZNF703 increases cisplatin efficacy. This study suggests that either ZNF703 alone or in conjunction with STK11 can be utilized to predict DFS in TNBC.

Background: Breast cancer (BC) is the most frequently diagnosed cancer in women and the leading cause of cancer-related deaths in women globally. Carriers of P/LP variants in the BRCA1, BRCA2, TP53, PTEN, CDH1, PALB2, and STK11 genes have an increased risk of developing BC, which is why more and more guidelines recommend prophylactic mastectomy in this group of patients. Because traditional genetic testing is expensive and can cause delays in patient management, radiomics based on diagnostic imaging could be an alternative. This study aims to evaluate whether ultrasound-based radiomics features can predict P/LP variant status in BC patients. Methods: This retrospective study included 88 breast tumors in patients tested with multigene panel tests, including all seven above-mentioned genes. Ultrasound images were acquired prior to any treatment, and the tumoral and peritumoral areas were used to extract radiomics data. The study population was divided into P/LP and non-P/LP variant groups. Radiomics features were analyzed using machine learning models, alone or in combination with clinical features, with the aim of predicting the genetic status of BC patients. Results: We observed significant differences in radiomics features between P/LP- and non-P/LP-variant-driven tumors. The developed radiomics model achieved a maximum mean accuracy of 85.7% in identifying P/LP variant carriers. Including features from the peritumoral area yielded the same maximum accuracy. Conclusions: Radiomics models based on ultrasound images of breast tumors may provide a promising alternative for predicting P/LP variant status in BC patients. This approach could reduce dependence on costly genetic testing and expedite the diagnostic process. However, further validation in larger and more diverse populations is needed.

One to 3% of gastric cancers are secondary to genetic predisposition, notably hereditary diffuse gastric cancers (HDGC) caused by CDH1 gene mutations. According to French recommendations, in case of CDH1 gene mutation, a prophylactic total gastrectomy should be performed between 20 and 30 years old. This gastrectomy should remove all the gastric mucosa at both extremities (duodenal and esophageal sides). Histopathological examinations of prophylactic total gastrectomies in asymptomatic CDH1-mutated patients reveal microscopic foci of diffuse-type cancer in 90 to 100% of cases. Lymph node involvement and lympho-vascular invasion are extremely rare, justifying the use of a D1-only lymphadenectomy. In the context of prophylaxis, limited lymphadenectomy and the development of minimally invasive oesogastric surgery, the minimally invasive approach might be the preferred approach, in expert centers. Surgical outcomes seem to be similar to those after gastrectomy for cancer. Prophylactic total gastrectomy is the cornerstone of CGDH management, associated with multidisciplinary follow-up and mammary surveillance in women.

Stomach cancer is one of the leading causes of cancer death, and its epidemiologic characteristics are regionally heterogeneous worldwide. The BRICS nations (Brazil, Russian Federation, India, China, and South Africa) have markedly increasing influences on the international stage. We aim to investigate time trends in stomach cancer mortality among the BRICS countries from 1982 to 2021.

Data for this study were obtained from the Global Burden of Disease (GBD) 2021 public dataset to investigate the deaths, all-age mortality rate, and age-standardized mortality rate (ASMR) of stomach cancer. The age-period-cohort (APC) model was employed to estimate net drift, local drift, age-specific curves, and period (cohort) relative risks, and the Bayesian generalized linear model was employed to evaluate the relationship between food intake and mortality rate.

In 2021, there were approximately 572,000 stomach cancer deaths across the BRICS, accounting for 59.9% of global death. Russian Federation exhibited the most significant reduction in ASMR of stomach cancer among the BRICS. In contrast, China continued to report the highest number of stomach cancer deaths. The risk of mortality associated with stomach cancer exhibited a marked increase with advancing age, both within these countries and at the global level. PUFA, sodium, calcium and trans fat may have an impact on the mortality rate of stomach cancer. Favorable trends in period and birth cohort effects were observed in these five nations over the past decades.

BRICS countries have made varying progress in reducing stomach cancer mortality. Given the diverse environments, it is recommended to progressively develop customized stomach cancer prevention strategies, utilizing available resources. Healthcare services should be extended to all age groups, with a particular emphasis on vulnerable populations.

Gastric cancer (GC) is one of the most fatal types of solid neoplasms involving individuals globally due to its chemo-resistant and metastatic nature. 5-Fluorouracil (5-FU) resistance is a complex procedure concerning the prognosis of patients with GC treated with this agent. Metformin has recently been highlighted as a member of anti-diabetic agents for its potential anti-cancer influences. In this study, we investigated the chemo-sensitivity and cell death mechanisms by which metformin moderates its effects by targeting ABCB1 (MDR1), DKK1, WNT5A, and chemo-resistance proteins (P-gp and CD44) on 5-FU-resistant gastric cancer cells. MTT assay exhibited that the combined metformin treatment with 5-FU had a more cytotoxic effect than 5-FU alone. DAPI staining proved that metformin, 5-FU, and co-treatment of them exerted an apoptotic effect on GC cells. Immunocytochemistry illustrated that metformin and its combination with 5-fluorouracil reduced the protein expressions of CD44 and P-gp, compared to the control group. The outcomes of this research displayed that the co-treatment of metformin with 5-FU significantly diminished the expressions of ABCB1, WNT5A, and DKK1 in comparison to the control. The co-treatment of these agents also decreased the expression of WNT5A and ABCB1 compared to 5-FU alone group. Overall, this study's findings demonstrated that co-treating metformin with 5-FU could overcome chemoresistance in GC cells by reducing the expression of WNT5A, MDR1, P-gp, and CD44 levels.

Gastric cancer (GC) is a significant worldwide health concern and is a leading cause of cancer-related mortality. Immunotherapy has arisen as a promising strategy to stimulate the patient's immune system in combating cancer cells. Nevertheless, the effectiveness of immunotherapy in individuals with gastric cancer (GC) is not yet optimal. Thus, it is crucial to discover biomarkers capable appof predicting the advantages of immunotherapy for tailored treatment. The tumor microenvironment (TME) and its constituents, including cancer-associated fibroblasts (CAFs), exert a substantial influence on immune responses and treatment outcomes. In this investigation, we utilized single-cell RNA sequencing to profile CAFs in GC and established a scoring method, referred to as the CAF score (CAFS), for the prediction of patient prognosis and response to immunotherapy. Through our analysis, we successfully identified distinct subgroups within CAFs based on CAF score (CAFS), namely CAFS-high and CAFS-low subgroups. Notably, we noted that individuals within the CAFS-high subgroup experienced a lessF favorable prognosis and displayed diminished responsiveness to immunotherapy in contrast to the CAFS low subgroup. Furthermore, we analyzed the mutation and immune characteristics of these subgroups, identifying differentially mutated genes and immune cell compositions. We established that CAFS could forecast treatment advantages in patients with gastric cancer, both for chemotherapy and immunotherapy. Its efficacy was additionally confirmed in contrast to other biomarkers, including Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenotypic Score (IPS). These findings emphasize the clinical relevance and potential utility of CAFS in guiding personalized treatment strategies for gastric cancer.

Bilateral risk-reducing mastectomy (BRRM) is the surgical removal of both breasts to reduce the risk of cancer. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, outcomes, and risks of BRRM to update the society's 2017 statement. We held a virtual meeting to outline key topics and conducted a literature search using PubMed to identify relevant articles. After literature review, recommendations were made according to group consensus. Individuals with a high lifetime risk of breast cancer due to pathogenic variants in high penetrance breast cancer-predisposition genes, early chest or breast radiation exposure, or a compelling family history should be counseled on the option of BRRM. However, BRRM is not recommended for most patients with high-risk lesions and may be contraindicated in patients who have other competing cancers and/or a high risk of surgical complications. BRRM effectively reduces the risk of breast cancer development, although the survival benefit is unclear. For patients with low-to-moderate breast cancer risk, alternative management strategies should be encouraged, including lifestyle modifications, high-risk screening, and risk-reducing medications. Discussions of BRRM should cover: (1) breast-cancer risk estimates; (2) the procedure's degree of risk reduction and impact on survival; (3) surgical techniques, potential surgical complications and long-term sequelae; and (4) alternatives to surgery. Surgeons should encourage shared and informed decision making with patients who have an elevated lifetime risk of developing breast 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.

Due to considerable tumour heterogeneity, stomach adenocarcinoma (STAD) has a poor prognosis and varies in response to treatment, making it one of the main causes of cancer-related mortality globally. Recent data point to a significant role for metabolic reprogramming, namely dysregulated lactic acid metabolism, in the evolution of STAD and treatment resistance. This study used a series of artificial intelligence-related approaches to identify IGFBP7, a Schlafen family member, as a critical factor in determining the response to immunotherapy and lactic acid metabolism in STAD patients. Computational analyses revealed that a high lactic metabolism (LM) state was associated with poor survival in STAD patients. Further biological network-based investigations identified a key subnetwork closely linked to LM. Machine learning techniques, such as random forest and least absolute shrinkage and selection operator, highlighted IGFBP7 as a crucial indicator in STAD. Functional annotations showed that IGFBP7 expression was linked to important immune and inflammatory pathways. In vitro experiments demonstrated that silencing IGFBP7 suppressed cell proliferation and migration. Furthermore, heightened susceptibility to several chemotherapeutic drugs was linked to elevated IGFBP7 levels. In conclusion, this work sheds light on the mechanisms by which the lactate metabolism-related indicator IGFBP7 affects the tumour immune milieu and the response to immunotherapy in STAD. The results point to IGFBP7 as a possible therapeutic target and predictive biomarker for the treatment of STAD.

Advanced gastric tumors are extremely prone to metastasize the in 20%-30% of gastric cancer, and patients have a poor prognosis despite systemic chemotherapy. Peritoneal metastases from gastric cancer usually indicate the end stage of the disease without curative treatment.

To peritoneal metastasis for facilitating clinical therapy are urgently needed.

Immunohistochemical staining and immunofluorescence staining were used to demonstrate the high expression of cathepsin L (CTSL) in human gastric cancer tissues and its localization in cells. Lentivirus transfection was used to construct stable cell lines. Transwell invasion assays, wound healing assays, and animal tests were used to determine the relationships between CTSL and epithelial-mesenchymal transition (EMT) and tumorigenic potential in vivo.

We observed that macrophage-derived CTSL promoted gastric cancer cell migration and metastasis via the EMT pathway in vitro and in vivo, which involved macrophage polarization. Our findings suggest that macrophages improve extracellular matrix remodeling and hence facilitate tumor metastasis. Ablation of CTSL in macrophages within the tumor microenvironment may improve tumor therapy and the prognosis of patients with gastric cancer peritoneal metastasis.

In consideration of our findings, tumor-associated macrophage-derived CTSL is an important factor that promotes the metastasis and invasion of gastric cancer cells, and the targeting of CTSL may potentially improve the prognosis of patients with gastric cancer with peritoneal metastasis.

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC.

Gastric cancer (GC) incidence has been decreasing over the last decades; however, there are uncertainties in trends and proportional distribution of the diffuse type.

GC incidence data were extracted from the population-based Friuli Venezia Giulia Cancer Registry. GC types (diffuse vs. others) were compared in relation to age at diagnosis, calendar years, and sexes.

Between 1995 and 2021, diffuse GC accounted for 10.2% of all GCs. The proportion was greater among individuals aged <45 years, 34.0% in women and 25.7% in men. An increasing proportion over time was observed, in particular in women (from 9.9% in 1995-2000 to 14.10% during 2011-2021). In the last decade (2011-2021), a decreased incidence of all GC was observed, reaching an age-standardized rate (world standard) of 1.4/100,000 for men and 1.2/100,000 for women. Rates of diffuse GC were 0.3/100,000 in younger population.

Although the overall GC incidence is decreasing, the percentage of diffuse GC is increasing in the younger population, particularly in women. Reasons for the increased proportion of diffuse-type GC within younger women remain uncertain, possibly related to the decreased exposure to risk factors for other GC histotypes.

Gastric cancer is a major cause of cancer-related death worldwide, despite the reduction in its incidence. The disease is still burdened with a poor prognosis, particularly in Western countries. The main risk factor is the infection by Helicobacter pylori, classified as a class I carcinogen by the IARC, and It is well-known that primary prevention of gastric cancer can be achieved with the eradication of the infection. Moreover, non-invasive measurement of pepsinogens (PGI and PGI/PGII ratio) allows the identification of patients that should undergo upper gastrointestinal (GI) endoscopy. Gastric non-cardia adenocarcinoma is indeed preceded by a well-defined precancerous process that involves consecutive stages, described for the first time by Correa et al. more than 40 years ago, and patients with advance stages of gastric atrophy/intestinal metaplasia and with dysplastic changes should be followed-up periodically with upper GI endoscopies. Despite these effective screening and surveillance methods, national-level screening campaigns have been adopted only in few countries in eastern Asia (Japan and South Korea). In this review, we describe primary and secondary preventive measures for gastric cancer, discussing the need to introduce screening also in Western countries. Moreover, we propose a simple algorithm for screening that could be easily applied in clinical practice.

Gastric cancer represents a significant global health challenge due to its high mortality and incidence rates, particularly in Eastern Asia, Eastern Europe, and South America. This comprehensive review synthesizes the latest epidemiological data and explores both modifiable and non-modifiable risk factors associated with gastric cancer, aiming to delineate the multifactorial etiology of this disease. Modifiable risk factors include Helicobacter pylori infection, obesity, dietary habits, smoking and alcohol consumption, whereas nonmodifiable factors comprise genetic predispositions, age, family history and male gender. The interplay of these factors significantly impacts the risk and progression of gastric cancer, suggesting potential preventive strategies. The challenges in treating gastric cancer are considerable, largely because of the late-stage diagnosis and the heterogeneity of the disease, which complicate effective treatment regimens. Current treatment strategies involve a combination of surgery, chemotherapy, radiotherapy, and targeted therapies. The FLOT regimen (5-FU, Leucovorin, Oxaliplatin and Docetaxel) is now a standard for resectable cases in Europe and the US, showing superior survival and response rates over ECF and ECX regimens. For HER2-positive gastric cancer, trastuzumab combined with chemotherapy improves overall survival, as demonstrated by the ToGA trial. Additionally, immune checkpoint inhibitors like pembrolizumab and nivolumab offer promising results. However, the five-year survival rate remains low, underscoring the urgency for improved therapeutic approaches. Recent advancements in molecular biology and cancer genomics have begun to pave the way for personalized medicine in gastric cancer care, focusing on molecular targeted therapies and immunotherapy. This review also highlights the critical need for better screening methods that could facilitate early detection and treatment, potentially improving the prognosis. By integrating epidemiological insights with new therapeutic strategies, this article aims to thoroughly understand of gastric cancer's dynamics and outline a framework for future research and clinical management, advocating for a multidisciplinary approach to tackle this formidable disease.

Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.

To describe gastric and breast cancer risk estimates for individuals with CDH1 variants.

Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.

Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.

A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).

Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Cancer susceptibility syndromes confer an increased lifetime risk of cancer and occur due to germline likely-pathogenic or pathogenic variants in a cancer susceptibility gene. Clinical Genetics services advise patients of ways to manage their future cancer risks, often prefaced with uncertainties due to poor understandings of individualised risk. For individuals/couples whose future offspring are at risk of a cancer susceptibility syndrome, different options are available depending on their preferences and circumstances, including prenatal diagnosis and preimplantation genetic testing. This review provides an overview of the most common cancer susceptibility syndromes, available reproductive options and a genetic counselling framework recommended to support individuals/couples in their decision-making. We describe complexities of decision-making involving moderate penetrance and sex-specific variable penetrance genes and explore associated ethical issues arising in this complex area of medicine.

Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.

The Golgi apparatus (GA), an organelle that processes, sorts, and transports proteins synthesized by the endoplasmic reticulum, is also involved in many cellular processes associated with cancer, such as angiogenesis, the innate immune response, and tumor invasion and migration. We aimed to construct a breast cancer (BC) prognosis prediction model based on GA-related genetic information to evaluate the prognosis of patients with BC more accurately than existing models and to stratify patients for clinical therapy. In this study, The Cancer Genome Atlas-breast invasive carcinoma was used as the training cohort, and the Molecular Taxonomy of Breast Cancer International Consortium cohort was used as the validation cohort. Using bioinformatics methods, we constructed a GA-related gene risk score (GRS). The GRS was used to divide BC patients into a high-GRS group and a low-GRS group, and functional analysis, survival analysis, mutation analysis, immune landscape analysis, and metabolic analysis were performed to compare the 2 groups. Finally, a nomogram was constructed for clinical application. The genes in the GRS model were mainly related to the glucose metabolism pathway, and the main mutations in the 2 groups of patients were mutations in TP53 and CHD1. The mutation rate in the high-GRS group was greater than that in the low-GRS group. The high GRS group had higher tumor immune activity glycolysis; the pentose phosphate pathway tended to be the dominant metabolic pathways in this group, while fatty acid oxidation and glutamine catabolism tended to be dominant in the low-GRS group. GA-related genes were used to construct a prediction model for BC patients and had high accuracy in predicting prognosis. The mutations associated with the GRS are mainly TP53 and CDH1. Interestingly, the GRS is correlated with glucose metabolism in terms of gene expression and functional enrichment. In summary, the role of GRS-related genes in glucose metabolism is worthy of further study.

Our understanding of hereditary breast and ovarian cancer has significantly improved over the past two decades. In addition to BRCA1/2, pathogenic variants in several other DNA-repair genes have been shown to increase the risks of breast and ovarian cancer. The magnitude of cancer risk is impacted not only by the gene involved, but also by family history of cancer, polygenic risk scores, and, in certain genes, pathogenic variant type or location. While estimates of breast and ovarian cancer risk associated with pathogenic variants are available, these are predominantly based on studies of high-risk populations with young age at diagnosis of cancer, multiple primary cancers, or family history of cancer. More recently, breast cancer risk for germline pathogenic variant carriers has been estimated from population-based studies. Here, we provide a review of the field of germline genetic testing and risk evaluation for hereditary breast and ovarian cancers in high-risk and population-based settings.

Hypopharyngeal squamous cell carcinoma (HSCC) is a malignant tumor of head and neck. It was verified that circ0005027 was downregulated in HSCC tissues. Here, we aimed to investigate the function and specific regulatory mechanism of circ0005027 in HSCC. Ten pairs tissues of HSCC and adjacent para-cancer were collected. Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) measured circ0005027, miR-548c-3p, and Cadherin 1 (CDH1) mRNA expression. CCK-8 analyzed cell proliferation viability. Flow cytometry assay detected cell cycle and apoptosis rate. Clonal formation assay measured the clonal ability. Transwell detected cell invasion ability. Western blot was performed to detect CDH1, LAST1, p-LAST1, MST1, p-MST1, YAP1, p-YAP1, TAZ and p-TAZ protein level. Dual-luciferase, RIP and RNA pull-down assay identified the target relationship among circ0005027, miR-548c-3p and CDH1. circ0005027 was decreased in tissues and FaDu cells of HSCC. Overexpression of circ0005027 inhibited cell viability, G1-S transition, clonal formation, and invasion and increased cell apoptosis. circ0005027 acted as a ceRNA and decreased circ0005027 enhanced the malignant process of FaDu cells through sponging miR-548c-3p and inhibiting CDH1 expression. Overexpression of CDH1 activated YAP1/TAZ pathway and inhibited the growth of HSCC in vitro. circ0005027 might act as a potential biomarker for the progression and prognosis prediction in HSCC by regulating miR-548c-3p/CDH1/ YAP1/TAZ signaling pathway.

Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

The clinicopathological risk factors in the prognosis of stage IV gastric cancer have been comprehensively studied. However, the influencing factors of stage IV gastric cancer prognosis at genomic and transcriptional levels have not been well defined.

The mutational and transcriptional data, along with demographic, clinicopathological and prognostic information of 44 stage IV gastric cancer patients were downloaded from the TCGA database. Univariate and multivariate analyses were performed to identify the significant risk factors and a Nomogram model was established to predict the patient prognosis.

TTN, TP53, FLG, LRP1B, SYNE1 and ARID1A were among the top mutated genes without hot-spot mutations. The mutational status of AHNAK2, ASCC3, DNAH3, DOP1A, MYLK, SIPA1L1, SORBS2, SYNE1 and ANF462 significantly stratified the patient prognosis. The transcription of several genes, such as AQP10, HOXC8/9/10, COL10A1/COL11A1, WNT7B, KRT17 and KLK6 was significantly up-regulated or down-regulated. Enrichment analysis on mutations and transcription revealed cell skeleton and membrane function, extracellular matrix function, HPV infection, and several cancer-related pathways as the main aberrancies. Univariate analyses revealed a series of significant factors stratifying patient prognosis, mainly including cancer location, several mutated genes and many up- or down-regulated genes. However, subsequent multivariate analysis revealed SYNE1 mutation, DNAH3 mutation, COMMD3 transcription level, and cancer location as the independent risk factors. A Nomogram model has been established with these significant risk factors to predict the patient prognosis. Further validation is needed to ensure the effectiveness of the model in real clinical practice.

Cancer location, along with the mutational status of SYNE1 and DNAH3 and the transcriptional level of COMMD3 were independent risk factors of stage IV gastric cancer. A Nomogram model was established with these factors for prognosis prediction.

Toll-like receptors (TLRs) are a family of transmembrane receptors that play key roles in identifying invading pathogens and activating innate immunity. TLR1 has been reported to be associated with the risk of gastric cancer (GC) but that was based on only a simple statistical analysis.

We genotyped the TLR1 in 526 GC patients to investigate the association between the variation and gastric cancer survival by the multiplex polymerase chain reaction and sequencing method. The rs4833095 variation (chr4:38798089 [GRCh38. p14], T > C) in the TLR1 gene was genotyped in 526 patients who underwent GC resection. The associations between genotype, survival, and recurrence were investigated. The potential role of TLR1 in stomach cancer was investigated using clinical data from formalin-fixed, paraffin-embedded tissue samples.

Patients with the T/C and C/C genotypes of rs4833095 had a lower risk of recurrence than those with the T/T genotype. Recurrence-free periods were substantially longer in patients with the T/C or C/C genotypes (22.6 and 22.3 months, respectively) than in those with the T/T genotype (20.7 months). Patients with the T/C or C/C genotype, low expression levels of VEGF1, high expression levels of ERBB2 and ERCC1, the absence of cancer nodules, a tumor size of less than 5 cm, and poor differentiation had a considerably reduced risk of recurrence.

TLR1 rs4833095 was correlated with the postresection prognosis of patients with gastric cancer, suggesting that TLR1 may have a role in the onset or progression of gastric cancer.

CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old).

After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed β-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling.

Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization.

Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy.

Germline DNA, obtained from peripheral blood, was analysed by NGS.

A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up.

This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.