Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives.

BACKGROUND: Familial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern. METHODS: Normal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts. RESULTS: The most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06). CONCLUSION: This study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

Co-occurrence of germline BRCA1 and CDH1 pathogenic variants.

INTRODUCTION: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer. RESULTS: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified. CONCLUSION: This complex situation is challenging for genetic counselling and management of at-risk individuals.

Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC).

INTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and ß-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Randomized controlled trial on efficacy of oligomeric formula (HINE E-GEL®) versus polymeric formula (MEIN®) enteral nutrition after esophagectomy for esophageal cancer with gastric tube reconstruction.

The efficacy of early enteral nutrition after esophageal cancer surgery has been reported. However, the choice of formula and management of diarrhea are important to achieve the goal of enhanced recovery after surgery. The aim of this study is to assess the frequency of diarrhea/completion rate of enteral nutrition regimen as primary endpoints and the postoperative nutritional status/body composition analysis/operative morbidity as secondary endpoints was compared between the two nutrition groups. Among the 122 patients who underwent esophagectomy for esophageal cancer between December 2015 and September 2017, 67 patients who met the eligibility criteria were randomly assigned to receive enteral nutrition with either HINE E-GEL® (HINE group; n = 33) or MEIN® (MEIN group; n = 34). The incidence of diarrhea was significantly lower in the HINE group (18.2 % vs. 64.7 %, P < 0.001). The score of Bristol scale of POD 6/7 was significantly lower in the HINE group (P = 0.019/P = 0.006, respectively). The completion rate of enteral nutrition regimen was significantly higher in the HINE group (97.4 % vs. 86.6 %, P = 0.002). The Controlling Nutritional Status scores and total protein levels at 6 months after surgery were significantly better in the HINE group (P = 0.030 and P = 0.023, respectively), indicating improved tendency in nutritional status in the HINE group. However, there were no significant differences in Prognostic Nutritional Index values, blood test results, rapid turnover proteins, body mass index, or body composition between the two groups. HINE E-GEL compared with MEIN may reduce the frequency of diarrhea, enabling patients to adhere to the scheduled enteral nutrition plan. Also, maintenance of nutritional status with HINE E-GEL was comparable or potentially better in some nutrition components to that with MEIN, indicating that HINE E-GEL can be an option for enteral nutrition following esophageal surgery to achieve the goal of successful completion of scheduled enteral nutrition and smooth transition to the normal diet.

Gastric cancer: somatic genetics as a guide to therapy.

Gastric cancer is the leading cause of cancer-related mortality across the world, with poor prognosis and a median overall survival of ≤12 months for advanced stage gastric cancer. Environmental, genetic and other predisposing factors contribute to the development of gastric cancer and a predominant factor was found to be infection of Helicobacter pylori Advances in understanding the deranged signalling pathways that are critical for normal cellular homeostasis helped in the development of novel drugs that target specific proteins and pathways to curtail the growth of gastric cancer. Genetic studies revealed several single nucleotide polymorphisms, chromosomal aberrations and epigenetic alterations that likely play a major role in elevating the susceptibility to develop gastric cancer. Methylation pattern of specific genes may likely prove to be a valid biomarker for early detection of gastric cancer, but much progress is needed to establish specific markers. Important developments have been made in targeting human epidermal growth factor receptor-2 and vascular endothelial growth factor receptor 2 for treating advanced gastro-oesophageal junction cancer, using specific monoclonal antibodies. Lack of efficacy with regard to targeting other signalling pathways including mesenchymal-epithelial transition/hepatocyte growth factor and mammalian target of rapamycin is probably due to suboptimal patient selection for these clinical trials, which is probably due to the lack of appropriate biomarkers, to decide on responsive patient population. Besides the development of antagonists for the cell growth-related signalling pathways, advances are also being made to tackle gastric cancer by immunotherapies, targeting immune check-points, which may hold promise for better treatment options in future.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study.

INTRODUCTION: CDH1 predisposes primarily to diffuse gastric cancer (DGC). Multiple DGC cases in a family, DGC at a young age in an individual or the combination of DGC andlobular breast cancer (LBC) in an individual or a family define the hereditary DGC syndrome (HDGC), and testing for germline CDH1 mutations is warranted in HDGC. METHODS AND RESULTS: We report all index cases from Ile-de-France in which a germline CDH1 mutation has been identified. Out of 18 cases, 7 do not fulfil the HDGC-defining criteria. Three of them are women who presented initially with bilateral LBC below age 50, without personal or family history of DGC, and who subsequently developed symptomatic DGC. DISCUSSION: Our series of CDH1 mutation carriers is the largest to date and demonstrates that LBC might be the first manifestation of HDGC. A personal or family history of multiple LBCs at a young age, even without DGC, should prompt CDH1 mutation screening. It is paramount to identify mutation carriers early, so that they can benefit from prophylactic gastrectomy before they develop symptomatic, highly lethal DGC. We recommend a revision of the HDGC-defining criteria and propose for consideration the name 'Hereditary Diffuse Gastric and Lobular Breast Cancer' instead of HDGC.

Periodontitis and the risk of oral, gastric and esophageal cancers: a two-sample Mendelian randomization study.

BACKGROUND: Periodontitis is a common oral disease and the chronic inflammation caused by it may influence the development of cancers in the upper gastrointestinal tract. Many observational studies have established a relationship between the two, but the results are not entirely consistent. METHODS: Two-sample MR was performed using publicly available genome-wide association studies data for periodontitis, oral, gastric and oesophagal cancers. The Inverse Variance Weighting (IVW) method serves as the primary method, with MR Egger, Weighted Median, Simple Model and Weighted Model Algorithm methods as complementary methods to assess genetic causal associations. Cochran Q-test, MR-Egger regression and MR polytropic residuals and outliers were used to assess heterogeneity and horizontal pleiotropy. RESULTS: IVW results did not support a causal association between periodontitis and oral (OR = 1.00, 95% CI: 1.00, 1.00) and oesophagal cancer (OR = 1.00, 95% CI: 1.00, 1.00). Similarly, there was again no causal association between periodontitis and gastric cancer, which was integrated with an OR of 1.04 (95% CI: 0.97, 1.12). Complementary method results were consistent with IVW and heterogeneity and horizontal pleiotropy were not found in most studies. CONCLUSIONS: The findings of our MR study do not support a causal relationship between periodontitis and oral, gastric and oesophagal cancers.

Helicobacter Pylori Detected in Tap Water of Peruvian Patients with Gastric Cancer.

OBJECTIVE: To evaluate the correlation between the presence of H. pylori in paired samples of tap water and gastric cancer (GC) lesion in Lima city (Peru). MATERIAL AND METHODS: Gastric tissue and tap-water samples were prospectively collected from 82 Gastric Cancer who lived in Lima. HspA and ureA genes were evaluated by qPCR in the samples.  Results: The median age of patients with GC was 63 years, 52.4% were men and stage-II in 36.6%. A home-living time> 10 years was reported in 84.1% of patients. Boiling water treatment was indicated in 85.4% of cases. H. pylori was detected in 69.5% of gastric tissues and in 12.2% of analyzed tap-water. There was no differences in gastric infection rates among those with or without water contamination (70% vs. 69.4%, p=0.971). Conclusion & Impact: H. pylori was found in tap-water samples, however, detection rates were lower than in gastric cancer samples. Other sources of infection transmission should be investigated.

Impacto del virus Epstein Barr en el cáncer gástrico en el Perú / Impact of the Epstein Barr virus on gastric cancer in Peru

El virus de Epstein Barr (VEB) es responsable del 10% del cáncer gástrico (CG) y se correlaciona con mejor tasa de sobrevida. En Perú, no existen estudios sobre prevalencia y características clínicas de CG VEB positivo. Objetivos: Determinar la prevalencia y las características clínico patológicas del CG VEB positivo. Materiales y métodos: 111 muestras de GC fueron examinadas centralmente por hibridización cromogénica in situ del RNA del VEB (EBER CISH). Resultados: El 8,4% de los casos fueron positivos para VEB. La mayoría de los casos VEB positivos tuvieron más de 60 años, varones y la localización, antro / píloro fue la más frecuente. La mayoría de los casos fueron de tipo intestinal y un patrón tubular con una tendencia a un mejor pronóstico en comparación con los casos de VEB negativo. Conclusión: CG VEB positivo es una entidad con una prevalencia de 8,4% en Perú con características clínicas y morfológicas distintivas.

Epstein Barr Virus (EBV) is responsible of 10% of Gastric Cancer (GC), correlating with better survival rates. In Peru, there were not studies about prevalence and clinical characteristics of CG EBV positive. Objective: Determine prevalence and clinicopathological characteristics of GC EBV positive. Materials and methods: 111 GC tumour samples were centrally screened by Chromogenic in situ hybridization (CISH) technique for EBV-encoded RNA (EBER) transcript. Results: 8.4% of cases were positive for EBV. Most cases EBV positive were more than 60 years old; male, antrum/pylorus had more frequent localizations. Most cases had an intestinal type and tubular patter and a tendency to better prognostic in comparison EBV negative cases. Conclusion: EBV positive GC is an entity with a prevalence of 8.4% in Peru with distinctive clinical and morphological characteristics.

Disección submucosa endoscópica de cáncer gástrico temprano transpilórico: Reporte de caso y revisión de la literatura / Endoscopic submucosal dissection of a transpyloric early gastric cáncer: A case report and literature review

La disección submucosa endoscópica (DSE) es una técnica endoscópica avanzada que logra la resección curativa de neoplasias superficiales del tracto gastrointestinal, consiguiendo exéresis en bloque con márgenes libres de neoplasia evitando una cirugía. Sin embargo, los tumores localizados en la unión esófago gástrica, o pilórica son técnicamente más complejos para resecar por DSE. Cuando una neoplasia asienta en el píloro las características anatómicas de esta región pueden afectar la adecuada valoración de los márgenes y la realización del procedimiento. Presentamos el caso de un paciente varón de 70 años a quien en una endoscopia digestiva alta se le evidencia una lesión plana elevada multilobulada de 18 mm x 10 mm, situada mayoritariamente en los 2 cuadrantes inferiores del canal pilórico y compromiso mínimo del cuadrante supero-posterior, abarca principalmente la vertiente gástrica del canal pilórico y se extiende hacia el duodeno. Por todo ello se decide realizar resección en bloque de la lesión con la técnica de disección submucosa endoscópica. Se empleó el sistema ERBEJET con una cuchilla de tipo Hybrid knife, inyección salina con azul de metileno diluido al 0,04% sobre el margen distal, complementándose la inyección submucosa con ácido hialurónico al 0,4%. Se utilizó un "capuchón" o dispositivo plástico distal transparente recto para poder traccionar la lesión y permitir visualizar anterógradamente los márgenes de resección, incluso de la porción intraduodenal, permitiendo una adecuada disección submucosa. Luego de comprobar hemostasia se constató la resección en bloque. La histopatología mostró un adenocarcinoma tubular medianamente diferenciado con bordes quirúrgicos libres de lesión. Gracias a la estrategia de DSE utilizada, nuestro paciente pudo beneficiarse de la resección curativa de su cáncer gástrico con preservación del órgano y con perfecta funcionalidad. Este caso, el primero descrito en el país, muestra el avance de la endoscopía terapéutica nacional.

The endoscopic sumucosal disection (ESD) is an advanced endoscopic technique that achieves the curative resection of superficial neoplasms of the gastrointestinal tract, getting block exeresis with margins free of neoplasia avoiding surgery. However, tumors located in the esophagogastric junction, or pylorus, are technically more complex to resect by ESD. When a neoplasm settles in the pylorus, the anatomical characteristics of this region can affect the adequate assessment of the margins and the performance of the procedure. We present the case of a 70-year-old male patient who, in a high digestive endoscopy, showed a flat multilobulated lesion of 18 mm x 10 mm, located mostly in the lower 2 quadrants of the pyloric canal and minimal compromise of the upper-posterior quadrant, it mainly covers the gastric side of the pyloric channel and extends into the duodenum. Therefore, it was decided to perform en bloc resection of the lesion with the endoscopic submucosal dissection technique. The ERBEJET system was used with a knife type Hybrid knife, saline injection with methylene blue diluted 0.04% on the distal margin, submucosal injection being complemented with 0.4% hyaluronic acid. A "capsule" or straight transparent distal plastic device was used to be able to pull the lesion and allow anterograde visualization of the margins of resection, including the intraduodenal portion, allowing adequate submucosal dissection. Histopathology showed a moderately differentiated tubular adenocarcinoma with surgical edges free of injury. Thanks to the DSE strategy used, our patient could benefit from the curative resection of his gastric cancer with preservation of the organ and with perfect functionality. This case, the first described in the country, shows the progress of national therapeutic endoscopy.

Características endoscópicas y patológicas del cáncer gástrico en un hospital público peruano / Endoscopic and pathological characteristics of gastric cancer in a Peruvian public hospital

RESUMEN Objetivo: Evaluar las características endoscópicas y patológicas del cáncer gástrico del Hospital Nacional Luis N. Sáenz entre 2008 y 2013. Materiales y métodos: Estudio observacional retrospectivo transversal. Se revisó los informes endoscópicos, de pacientes mayores a 30 años, se ingresó al estudio el diagnóstico histológico de adenocarcinoma gástrico, las variables patológicas como tipo histológico, presencia deH. pylori y de metaplasia intestinal e incompleta. Resultados: Se identificó 92 casos de adenocarcinoma gástrico. Prevalencia promedio 0,6%, prevalencia de 0,34% en 2009 y 0,82% en 2013, sexo masculino 62%, femenino 38%, edad menor de 55 años 16%, mayor a 76 años 42%; presentación endoscópica Borrmann III 57%, II 16,3%, IV 15%, V 7,6%, I 3,3%; presentación distal 8 veces más frecuente que la proximal, tipo histológico intestinal 75%, H. pylori presente en 50% casos, metaplasia intestinal en 40% de casos de cáncer gástrico. Conclusiones: Se encontró una alta prevalencia de cáncer gástrico. Frecuente en sexo masculino y en mayores de 76 años, presentación endoscópica más frecuente fue Borrmann III, la presencia de H. pylori y metaplasia intestinal incompleta asociada a cáncer tipo intestinal

ABSTRACT Objective: The endoscopic and pathological characteristics of gastric cancer in Luis N. Sáenz National Hospital between 2008 and 2013. Materials and methods: retrospective cross-sectional observational study. We reviewed the endoscopic reports of patients older than 30 years, we studied the histological diagnosis of gastric adenocarcinoma, pathological variables such as histological type, presence of H. pylori and complete and incomplete intestinal metaplasia. Results: 92 cases of gastric adenocarcinoma were identified. Average prevalence 0.6%, 0.34% in 2009 and 0.82% in 2013; 62% male, 38% female, age less than 55 years 16%, greater than 76 years 42%; endoscopic presentation Borrmann III 57%, II 16.3%, IV 15%, V 7.6%, I 3.3%; 8 times most frequent presentations distal the proximal v, 75% histologic intestinal type, H. pylori in 50% cases, intestinal metaplasia in 40% of cases of gastric cancer. Conclusion: We found high prevalence of gastric cancer. Common in males, and in people over 76, more frequent endoscopic presentation was Borrmann III, the presence of H. pylori and incomplete intestinal metaplasia associated with intestinal cancer type.

Outcome as a measure of quality of care in oncology: experience at sultan qaboos university hospital, oman.

OBJECTIVES: Measurement of outcomes is increasingly employed as an indicator of the quality of clinical care. The most commonly measured outcome in many clinical studies, especially in oncology, still remains the overall survival rate. Sultan Qaboos University Hospital (SQUH), Oman, is striving for excellence through quality management. In seeking continual improvement, quality measurement exercises have been initiated throughout the Hospital. We present the overall survival rate of four of the ten most common cancers diagnosed in Oman. METHODS: The cancers included non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), breast cancer, and stomach cancer. The studies were all retrospective and had been conducted previously. For present purposes, only the overall survival was compared with studies both from the region, and with bench-mark studies. RESULTS: For NHL, with a median follow-up of 8 months, the 2-year overall survival rate was 64%; 90% for low risk, 55% for intermediate risk, and 15% for high risk groups. For HL, the 5-year overall survival rate was 64%; 76% for low risk and 42% for high risk. For breast cancer, the 5-year survival rate was 67%; percentages were 88%, 75% and 59% for Groups I, II, and III respectively. For gastric cancer, the 5-year survival rate was 16.5 %; 24% for the non-metastatic group. CONCLUSION: The outcome of patients with early stages and fewer adverse prognostic factors is comparable to what has been reported in the international literature; however, the outcome is inferior for patients presenting with advanced stage disease and several adverse prognostic factors.