HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches.

Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of ≥1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.

Morphologic heterogeneity of carcinoma with signet ring cell features at different primary sites.

INTRODUCTION: Signet-ring-cells (SRC) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features which can aid in identifying the site of origin. METHODS: the series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, n=38), stomach (n=48), pancreatobiliary system (n=16), colorectum (n=40), appendix (n=32), breast (n=41), and lung (n=42). H&E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software. RESULTS: extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) ratio, whereas appendiceal carcinoma the lowest. CONCLUSION: morphological evaluation (extracellular mucin, architectural patterns and the nature of cytoplasmic mucin/vacuole) represent an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guide further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms.

Gastric polyps in Familial Adenomatous Polyposis Portuguese patients: the first Western cohort with Asian features.

INTRODUCTION: Chronic atrophic gastritis may contribute to gastric polyps (GP) phenotype in familial adenomatous polyposis (FAP). Considering the high prevalence of Helicobacter-pylori (HP) infection in Portugal, we aim to characterise GP in a series of Portuguese patients. METHODS: In a retrospectively-selected series of 53 FAP patients, clinical data and histopathological features of GP and background gastric mucosa were studied. SPSS (27.0) was used for statistical analysis. RESULTS: Thirteen patients (24.5%) developed fundic gland polyps (FGP), seven (13.2%) gastric adenomas (GA) and ten (18.9%) both FGP and GA. Out of 100 GP, four were hyperplastic polyps, 58 FGP (24 with dysplasia), 35 intestinal-type GA (intGA) and three foveolar-type GA (fovGA). IntGA were larger (60% >7mm, p=0.03), occurred predominantly in the distal stomach (66.7%, p=0.024), in patients harbouring gastric intestinal metaplasia (IM) (86.7%, p<0.001) and duodenal adenomas (86.7%, p<0.001) Conclusion: This is the first Western series showing high prevalence of intGA in FAP patients, comparable to Asian cohorts. HP infection and chronic atrophic gastritis/intestinal metaplasia are likely responsible for this difference, with risk of neoplastic transformation and management implications. Biopsy/excision of GP >7mm, in the distal stomach, and in patients harbouring gastric intestinal metaplasia/duodenal adenomas should be considered.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer.

Cadherins are cell-cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. CDH1 and CDH3 mRNA expression was obtained from 42 gastric tumours' RNA-seq data. CRISPR-Cas9 was used to knock out CDH1 and a putative regulatory element. CDH1-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a CDH1 promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess CDH1/E-cadherin and CDH3/P-cadherin expression. In 42% of gastric tumours analysed, CDH1 to CDH3 switch was observed. CDH1 knockout triggered CDH1/E-cadherin complete loss and CDH3/P-cadherin expression increase at plasma membrane. This switch, likely rescuing adherens junctions, increased cell migration/proliferation, commonly observed in aggressive tumours. E- to P-cadherin switch accompanied increased CDH1 promoter interactions with CDH3-eQTL, absent in normal stomach and parental cells. CDH3-eQTL deletion promotes CDH3/CDH1 reduced expression. These data provide evidence that loss of CDH1/E-cadherin expression alters the CDH3 locus chromatin conformation, allowing a CDH1 promoter interaction with a CDH3-eQTL, and promoting CDH3/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.

Role of Endoscopic Biopsies and Morphologic Features in Predicting Microsatellite Instability Status in Gastric Cancer: A Multicenter Comparative Study of Endoscopic Biopsies and Surgical Specimens.

Evaluation of mismatch repair (MMR) protein and microsatellite instability (MSI) status plays a pivotal role in the management of gastric cancer (GC) patients. In this study, we aimed to evaluate the accuracy of gastric endoscopic biopsies (EBs) in predicting MMR/MSI status and to uncover histopathologic features associated with MSI. A multicentric series of 140 GCs was collected retrospectively, in which EB and matched surgical specimens (SSs) were available. Laurén and WHO classifications were applied and detailed morphologic characterization was performed. EB/SS were analyzed by immunohistochemistry (IHC) for MMR status and by multiplex polymerase chain reaction (mPCR) for MSI status. IHC allowed accurate evaluation of MMR status in EB (sensitivity: 97.3%; specificity: 98.0%) and high concordance rates between EB and SS (Cohen κ=94.5%). By contrast, mPCR (Idylla MSI Test) showed lower sensitivity in evaluating MSI status (91.3% vs. 97.3%), while maintaining maximal specificity (100.0%). These results suggest a role of IHC as a screening method for MMR status in EB and the use of mPCR as a confirmatory test. Although Laurén/WHO classifications were not able to discriminate GC cases with MSI, we identified specific histopathologic features that are significantly associated with MMR/MSI status in GC, despite the morphologic heterogeneity of GC cases harboring this molecular phenotype. In SS, these features included the presence of mucinous and/or solid components ( P =0.034 and <0.001) and the presence of neutrophil-rich stroma, distant from tumor ulceration/perforation ( P <0.001). In EB, both solid areas and extracellular mucin lakes were also discriminating features for the identification of MSI-high cases ( P =0.002 and 0.045).

Performance of Immunohistochemical and Molecular Methods in Detecting Microsatellite Instability in Gastric Cancer: A Multicenter Study.

INTRODUCTION: Microsatellite instability (MSI) is an important prognostic molecular biomarker for gastric cancer (GC). MSI status may be detected by immunohistochemistry (IHC) for mismatch repair (MMR) proteins and polymerase chain reaction (PCR). Idylla™ MSI assay has not been validated for GC but may prove to be a valid alternative. METHODS: In a series of 140 GC cases, MSI status was evaluated by IHC for MLH1, PMS2, MSH2, and MSH6; gold-standard pentaplex PCR panel (PPP) (BAT-25, BAT-26, NR-21, NR-24, and NR-27); and Idylla. Statistical analysis was performed using SPSS 27.0. RESULTS: PPP identified 102 microsatellite stable (MSS) cases and 38 MSI-high cases. Only 3 cases showed discordant results. Compared with PPP, the sensitivity was 100% for IHC and 94.7% for Idylla. Specificity was 99% for IHC and 100% for Idylla. MLH1 IHC alone showed sensitivity and specificity of 97.4% and 98.0%, respectively. IHC identified three indeterminate cases; all were MSS according to PPP and Idylla. CONCLUSION: IHC for MMR proteins represents an optimal screening tool for MSI status in GC. If resources are limited, isolated MLH1 evaluation may constitute a valuable option for preliminary screening. Idylla may help detect rare MSS cases with MMR-loss and define MSI status in indeterminate cases.

DOES NEOADJUVANT CHEMORADIOTHERAPY FOR ESOPHAGEAL AND GASTROESOPHAGEAL JUNCTION CANCER PATIENTS AFFECT POSTOPERATIVE OUTCOMES? A STUDY USING THE BECKER TUMOR REGRESSION GRADE SYSTEM AND LYMPH NODE REGRESSION.

BACKGROUND: The effect of neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal cancer can be determined by assessing the Becker tumor regression grade in the primary tumor, as well as in lymph nodes. AIMS: The aim of this study was to investigate the anatomopathological changes caused by neoadjuvant chemoradiotherapy and their impact on clinical parameters. Specifically, we analyzed the Becker tumor regression grade, lymph node status, and regression changes and evaluated their association with the Clavien-Dindo classification of surgical complications and overall patient survival. METHODS: This is a retrospective and observational study including 139 patients diagnosed with adenocarcinoma or squamous cell carcinoma of the esophagus and treated with either neoadjuvant chemoradiotherapy followed by surgery or surgery alone. For the 94 patients who underwent neoadjuvant chemoradiotherapy, we evaluated tumor regression by Becker tumor regression grade in primary tumors. We also analyzed lymph node status and regression changes on lymph nodes with or without metastases. Overall survival analysis was performed using Kaplan-Meier curves. RESULTS: Becker tumor regression grade is associated with lower lymphatic permeation (p<0.01) and vascular invasion (p<0.001), but not with lymph node regression rate (p=0.10). Clavien-Dindo classification was associated neither with lymph node regression rate (odds ratio=0.784, p=0.795) nor with tumor regression grade (p=0.68). Patients who presented with lymphatic permeation and vascular invasion had statistically significantly lower median survival (17 vs. 30 months, p=0.006 for lymphatic permeation, and 14 vs. 29 months, p=0.024 for vascular invasion). CONCLUSION: In our series, we were unable to demonstrate an association between Becker tumor regression grade and lymph node regression rate with any postoperative complications. Patients with lower lymphatic permeation and vascular invasion have higher overall survival, correlating with a better response in the Becker tumor regression grade system.

Primary small bowel follicular lymphoma: the role of balloon-assisted enteroscopy in diagnosis and follow-up.

An asymptomatic 38-year-old male with no significant previous medical history performed routine laboratory studies that revealed iron-deficiency anemia. Esophagogastroduodenoscopy and colonoscopy were unremarkable and he undergone videocapsule endoscopy that revealed multiple small polyps along jejunum and ileum. Double-balloon enteroscopy confirmed the presence of scattered small whitish nodules and small polyps carpeting segments of jejunal mucosal and sometimes forming conglomerates with a nodular appearance. Histopathological examination showed lamina propria expansion by neoplastic follicles, predominantly composed by small lymphoid cells that, by immunohistochemistry, showed expression of CD20, CD10 and bcl-2. Computed tomography scan of abdomen and pelvis did not reveal systemic involvement, consistent with primary small bowel follicular lymphoma. Chemotherapy was started and, at reevaluation enteroscopy, although nodular jejunal segments persisted, biopsies did not show involvement by lymphoproliferative disease, which was interpreted as complete remission. Periodic clinical and biochemical evaluation and annual enteroscopic surveillance was maintained and, after three years, local recurrence of low-grade follicular lymphoma was detected. As previously, there was no evidence of systemic involvement and the decision was to maintain close surveillance. After one year, the patient remains asymptomatic and without evidence of disease progression. This case illustrates the essential role of balloon-assisted enteroscopy for diagnosis and surveillance of primary small bowel follicular lymphoma.

Acute gastrointestinal graft-versus-host disease with cytomegalovirus and Epstein-Barr virus superinfection in a patient with COVID-19.

A 60-year-old female was diagnosed with acute myeloid leukemia. After initial remission with chemotherapy, she relapsed and underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two months later, she presented to emergency department with watery diarrhea, abdominal pain and fever. She also tested positive for SARS-CoV2 on nasopharyngeal swab by polymerase chain reaction (PCR) and both cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were detected in peripheral blood. Flexible sigmoidoscopy showed diffuse edema, erythema and loss of vascular pattern with interspersed segments of mucosal denudation and exudate and bBiopsies revealed epithelial cell apoptosis, diffuse crypt atrophy and dropout, with ulceration and both CMV and EBV were detected in colon mucosa, consistent with acute severe gastrointestinal graft-versus-host disease complicated by CMV and EBV superinfection. Despite starting therapy with methylprednisolone, ganciclovir and rituximab,she presented unfavorable evolution and died after 5 weeks.

A practical approach for PD-L1 evaluation in gastroesophageal cancer.

PD-L1 is an established predictive immunohistochemical biomarker of response to immune checkpoint inhibitors. At present, PD-L1 is routinely assessed on biopsy samples of advanced gastroesophageal cancer patients before initiating first-line treatment. However, PD-L1 is still a suboptimal biomarker, due to changing cut-off values and scoring systems, interobserver and interlaboratory variability.This practical illustrated review discusses the range of staining patterns of PD-L1 and the potential pitfalls and challenges that can be encountered when evaluating PD-L1, focusing on gastric and gastroesophageal adenocarcinoma (G/GEA) and esophageal squamous cell carcinoma (ESCC).

Does neoadjuvant chemoradiotherapy for esophageal and gastroesophageal junction cancer patients affect postoperative outcomes? a study using the becker tumor regression grade system and lymph node regression / A radioterapia e quimioterapia neoadjuvantes para pacientes com câncer de esôfago e junção gastro-esofágica afetam os resultados pós-operatórios? um estudo usando o sistema de regressão tumoral de becker e regressão de linfonodos

ABSTRACT BACKGROUND: The effect of neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal cancer can be determined by assessing the Becker tumor regression grade in the primary tumor, as well as in lymph nodes. AIMS: The aim of this study was to investigate the anatomopathological changes caused by neoadjuvant chemoradiotherapy and their impact on clinical parameters. Specifically, we analyzed the Becker tumor regression grade, lymph node status, and regression changes and evaluated their association with the Clavien-Dindo classification of surgical complications and overall patient survival. METHODS: This is a retrospective and observational study including 139 patients diagnosed with adenocarcinoma or squamous cell carcinoma of the esophagus and treated with either neoadjuvant chemoradiotherapy followed by surgery or surgery alone. For the 94 patients who underwent neoadjuvant chemoradiotherapy, we evaluated tumor regression by Becker tumor regression grade in primary tumors. We also analyzed lymph node status and regression changes on lymph nodes with or without metastases. Overall survival analysis was performed using Kaplan-Meier curves. RESULTS: Becker tumor regression grade is associated with lower lymphatic permeation (p<0.01) and vascular invasion (p<0.001), but not with lymph node regression rate (p=0.10). Clavien-Dindo classification was associated neither with lymph node regression rate (odds ratio=0.784, p=0.795) nor with tumor regression grade (p=0.68). Patients who presented with lymphatic permeation and vascular invasion had statistically significantly lower median survival (17 vs. 30 months, p=0.006 for lymphatic permeation, and 14 vs. 29 months, p=0.024 for vascular invasion). CONCLUSION: In our series, we were unable to demonstrate an association between Becker tumor regression grade and lymph node regression rate with any postoperative complications. Patients with lower lymphatic permeation and vascular invasion have higher overall survival, correlating with a better response in the Becker tumor regression grade system.

RESUMO RACIONAL: O efeito da quimioradioterapia neoadjuvante em pacientes com câncer de esôfago localmente avançado pode ser determinado pela avaliação do grau de regressão tumoral de Becker no tumor primário, bem como nos linfonodos. OBJETIVOS: Investigar as alterações anatomopatológicas causadas pela quimioradioterapia neoadjuvante e seu impacto nos parâmetros clínicos. Especificamente, analisamos o grau de regressão tumoral de Becker, o status linfonodal e as alterações de regressão e avaliamos sua associação com a Classificação Clavien-Dindo de complicações cirúrgicas e a sobrevida geral dos pacientes. MÉTODOS: Estudo retrospectivo e observacional incluindo 139 pacientes diagnosticados com carcinoma espinocelular de esôfago ou adenocarcinoma da junção esofagogástrica, tratados com quimioradioterapia neoadjuvante seguido de cirurgia ou cirurgia isolada. Para os 94 pacientes submetidos a quimioradioterapia neoadjuvante, avaliamos a grau de regressão tumoral de Becker em tumores primários. Também analisamos o status linfonodal e as alterações de regressão em linfonodos com ou sem metástases. A análise de sobrevida global foi realizada usando curvas de Kaplan-Meier. RESULTADOS: O grau de regressão tumoral de Becker está associado a menor permeação linfática (p<0,01) e invasão vascular (p<0,001), mas não à taxa de regressão linfonodal (p=0,10). A classificação de Clavien-Dindo não foi associada à taxa de regressão linfonodal (OR=0,784; p=0,795) nem ao grau de grau de regressão tumoral (p=0,68). Os pacientes que apresentavam permeação linfática e invasão vascular tiveram sobrevida mediana menor estatisticamente significativa (17 vs 30 meses; p=0,006 para a permeação linfátiva e 14 vs 29 meses; p=0,024, para a invasão vascular, respectivamente). CONCLUSÕES: Em nossa série não conseguimos demonstrar associação entre grau de regressão tumoral de Becker e taxa de regressão linfonodal com quaisquer complicações pós-operatórias. Pacientes com menor permeação linfática e invasão vascular apresentam maior sobrevida global, correlacionando-se com uma melhor resposta no sistema Becker.

PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application.

Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma).In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.

Activation of Laminin γ2 by Helicobacter pylori Promotes Invasion and Survival of Gastric Cancer Cells With E-Cadherin Defects.

BACKGROUND: Helicobacter pylori infection induces cellular phenotypes relevant for cancer progression, namely cell motility and invasion. We hypothesized that the extracellular matrix (ECM) could be involved in these deleterious effects. METHODS: Microarrays were used to uncover ECM interactors in cells infected with H. pylori. LAMC2, encoding laminin γ2, was selected as a candidate gene and its expression was assessed in vitro and in vivo. The role of LAMC2 was investigated by small interference RNA (siRNA) combined with a set of functional assays. Laminin γ2 and E-cadherin expression patterns were evaluated in gastric cancer cases. RESULTS: Laminin γ2 was found significantly overexpressed in gastric cancer cells infected with H. pylori. This finding was validated in vitro by infection with clinical isolates and in vivo by using gastric biopsies of infected and noninfected individuals. We showed that laminin γ2 overexpression is dependent on the bacterial type IV secretion system and on the CagA. Functionally, laminin γ2 promotes cell invasion and resistance to apoptosis, through modulation of Src, JNK, and AKT activity. These effects were abrogated in cells with functional E-cadherin. CONCLUSIONS: These data highlight laminin γ2 and its downstream effectors as potential therapeutic targets, and the value of H. pylori eradication to delay gastric cancer onset and progression.

EBV and MSI Status in Gastric Cancer: Does It Matter?

We investigated the impactof microsatellite instability (MSI) and Epstein-Barr virus (EBV) status in gastric cancer (GC), regarding response to perioperative chemotherapy (POPChT), overall survival (OS), and progression-free survival (PFS). We included 137 cases of operated GC, 51 of which were submitted to POPChT. MSI status was determined by multiplex PCR and EBV status by EBV-encoded RNA in situ hybridization. Thirty-seven (27%) cases presented as MSI-high, and seven (5.1%) were EBV+. Concerning tumor regression after POPChT, no differences were observed between the molecular subtypes, but females were more likely to respond (p = 0.062). No significant differences were found in OS or PFS between different subtypes. In multivariate analysis, age (HR 1.02, IC 95% 1.002-1.056, p = 0.033) and positive lymph nodes (HR 1.82, IC 95% 1.034-3.211, p = 0.038) were the only prognostic factors for OS. However, females with MSI-high tumors treated with POPChT demonstrated a significantly increased OS compared to females with MSS tumors (p = 0.031). In conclusion, we found a high proportion of MSI-high cases. MSI and EBV status did not influence OS or PFS either in patients submitted to POPChT or surgery alone. However, superior survival of females with MSI-high tumors suggests that sex disparities and molecular classification may influence treatment options in GC.

Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes.

Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.

Comparison of East-Asia and West-Europe cohorts explains disparities in survival outcomes and highlights predictive biomarkers of early gastric cancer aggressiveness.

Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin_abnormal and CD44v6_very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin_abnormal/CD44v6_very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy.