Mutations in Helicobacter pylori infected patients with chronic gastritis, intestinal type of gastric cancer and familial gastric cancer.

BACKGROUND: Development of sequential changes of mucous leading to gastric cancer and familial cases of gastric cancer of intestinal type is widely connected with Helicobacter pylori infections. In this study we analysed variants of genes involved in cancerogenesis and inflammatory processes of intestines in patients infected with H.pylori. Our goal was to test whether mutations in these genes predestinate to development of gastric cancer, and whether there is a genetic factor that makes it more likely for infections with H.pylori to cause gastric cancer. As infections with H. pylori are relatively common, discovering such genetic predispositions could be used for establishing risk-groups and for planning treatments. METHODS: Our studies cover analysis of variants in genes involved in cancerogenesis: TP53 (rs11540652, rs587782329, COSM10771), MSH2 (rs193922376), MLH1 (rs63750217), and inflammatory processes of intestine: NOD2 (rs2066847, rs2066842), IL1A (rs1800587) and IL1B (rs1143634) from H.pylori-infected patients. RESULTS: Mutations were more common in the group of patients with gastric cancer of intestinal type and familial cases of gastric cancer in comparison with patients with chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer (p-value = 0.00824), with the prevalence of p53 mutations in patients with familial gastric cancer vs. patients with other changes of mucosa (p-value = 0.000049). Additionally, gastric cancer patients have mainly genotype TT or CT of the rs2066842 variant of the NOD2 gene. CONCLUSIONS: The lack of statistically significant changes of other interleukin genes involved in inflammatory processes may suggest the presence of H.pylori infection as a potential trigger for the development of the inflammatory process of the mucosa, leading through microbiota dysbiosis to the development of enteric gastric cancer. Mutations in analysed genes correlated with more severe mucosal changes, with a much more frequent presence of TP53 gene mutations, with a limited presence of other mutations in the familial history of gastric cancer.

Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer.

Purpose: Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression. Materials and Methods: Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing (WES) on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation and enrichment analysis were performed. Results: As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoAR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families. Conclusion: The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

Helicobacter pylori Status May Differentiate Two Distinct Pathways of Gastric Adenocarcinoma Carcinogenesis.

BACKGROUND: We evaluated the phenotype of sporadic gastric cancer based on HP status and binding of a tumor risk marker monoclonal, Adnab-9. METHODS: We compared a familial GC kindred with an extremely aggressive phenotype to HP-positive (HP+) and -negative (HP-) sporadic gastric adenocarcinoma (GC) patients in the same community to determine if similar phenotypes exist. This might facilitate gene discovery to understand the pathogenesis of aggressive GC phenotypes, particularly with publications implicating immune-related gene-based signatures, and the development of techniques to gauge the stance of the innate immune system (InImS), such as the FERAD ratio (blood ferritin:fecal Adnab-9 binding OD-background binding). Resection specimens for the sporadic and familial group were stained for HP and examined for intestinal metaplasia (IM) and immunostaining for Adnab-9. Familial kindred specimens were also tested for the E-cadherin mutation and APC (adenomatous polyposis coli). Survival was evaluated. RESULTS: Of 40 GC patients, 25% were HP+ with a greater proportion of intestinal metaplasia (IM) and gastric atrophy than the HP- group. The proband of the familial GC kindred, a 32-year-old mother with fatal GC, was survived by 13-year-old identical twins. Twin #1 was HP- with IM and Twin #2 was HP+. Both twins subsequently died of GC within two years. The twins did not have APC or E-cadherin mutations. The mean overall survival in the HP+ sporadic GC group was 2.47 ± 2.58 years and was 0.57 ± 0.60 years in the HP- group (p = 0.01). Survival in the kindred was 0.22 ± 0.24 years. Adnab-9 labeling was positive in fixed tissues of 50% of non-familial GC patients and in gastric tissue extract from Twin #2. The FERAD ratio was determined separately in six prospectively followed patient groups (n = 458) and was significantly lower in the gastric cancer patients (n = 10) and patients with stomach conditions predisposing them to GC (n = 214), compared to controls (n = 234 patients at increased risk for colorectal cancer but without cancer), suggesting a failure of the InImS. CONCLUSION: The HP+ sporadic GC group appears to proceed through a sequence of HP infection, IM and atrophy before cancer supervenes, and the HP- phenotype appear to omit this sequence. The familial cases may represent a subset with both features, but the natural history strongly resembles that of the HP- group. Two different paths of carcinogenesis may exist locally for sporadic GC. The InImS may also be implicated in prognosis. Identifying these patients will allow for treatment stratification and early diagnosis to improve GC survival.

Familial and hereditary gastric cancer, an overview.

There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.

A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients.

BACKGROUND: Approximately 10% of patients with gastric cancer (GC) have a genetic predisposition toward the disease. However, there is scant knowledge regarding germline mutations in predisposing genes in the Chinese GC population. This study aimed to determine the spectrum and distribution of predisposing gene mutations among Chinese GC patients known to have hereditary high-risk factors for cancer. METHODS: A total of 40 GC patients from 40 families were recruited from seven medical institutions in China. Next-generation sequencing was performed on 171 genes associated with cancer predisposition. For probands carrying pathogenic/likely pathogenic germline variants, Sanger sequencing was applied to validate the variants in the probands as well as their relatives. RESULTS: According to sequencing results, 25.0% (10/40) of the patients carried a combined total of 10 pathogenic or likely pathogenic germline variants involving nine different genes: CDH1 (n = 1), MLH1 (n = 1), MSH2 (n = 1), CHEK2 (n = 1), BLM (n = 1), EXT2 (n = 1), PALB2 (n = 1), ERCC2 (n = 1), and SPINK1 (n = 2). In addition, 129 variants of uncertain significance were identified in 27 patients. CONCLUSIONS: This study indicates that approximately one in every four Chinese GC patients with hereditary high risk factors may harbor pathogenic/likely pathogenic germline alterations in cancer-susceptibility genes. The results further indicate a unique genetic background for GC among Chinese patients.

Gastric cancer screening in low incidence populations: Position statement of AEG, SEED and SEAP. / Documento de posicionamiento de la AEG, la SEED y la SEAP sobre cribado de cáncer gástrico en poblaciones con baja incidencia.

This positioning document, sponsored by the Asociación Española de Gastroenterología, the Sociedad Española de Endoscopia Digestiva and the Sociedad Española de Anatomía Patológica, aims to establish recommendations for the screening of gastric cancer (GC) in low incidence populations, such as the Spanish. To establish the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We obtained a consensus among experts using a Delphi method. The document evaluates screening in the general population, individuals with relatives with GC and subjects with GC precursor lesions (GCPL). The goal of the interventions should be to reduce GC related mortality. We recommend the use of the OLGIM classification and determine the intestinal metaplasia (IM) subtype in the evaluation of GCPL. We do not recommend to establish endoscopic mass screening for GC or Helicobacter pylori. However, the document strongly recommends to treat H.pylori if the infection is detected, and the investigation and treatment in individuals with a family history of GC or with GCPL. Instead, we recommend against the use of serological tests to detect GCPL. Endoscopic screening is suggested only in individuals that meet familial GC criteria. As for individuals with GCPL, endoscopic surveillance is only suggested in extensive IM associated with additional risk factors (incomplete IM and/or a family history of GC), after resection of dysplastic lesions or in patients with dysplasia without visible lesion after a high quality gastroscopy with chromoendoscopy.

Total Gastrectomy for CDH-1 Mutation Carriers: An Institutional Experience.

BACKGROUND: Gastric cancer is a leading cause of cancer-related death across the world. A subset of gastric cancers demonstrates an inherited genetic predisposition. Individuals with germline mutations in the CDH1 gene incur a lifetime risk for diffuse gastric cancer and benefit from prophylactic gastrectomy. The results for this operative intervention remain relatively undescribed in the literature, despite guidelines supporting its use. METHODS: We present a single-institution series of patients with confirmed CDH1 mutations who underwent gastrectomy. We describe their presenting symptoms, preoperative screening, clinicopathologic features, and outcomes. Focal outcomes of interest are weight loss and postoperative morbidity. RESULTS: Between 2010 and 2018, ten patients with a confirmed CDH1 mutation underwent total gastrectomy with intestinal pouch reconstruction at our institution. Two patients had clinical gastric cancer at the time of their operation at 21 and 60 y of age. Eight patients had prophylactic gastrectomy. All prophylactic patients had undergone prior endoscopic screening without detection of cancer; however, three had occult gastric cancer on pathological examination. Median weight loss after gastrectomy was 10 kg at 6 mo and 11 kg at 1 y. Postoperative morbidity was limited to one anastomotic leak, one hematoma, and one case of pneumonia. All patients remain disease-free with median follow-up of 19 mo. CONCLUSIONS: Total gastrectomy for patients with a CDH1 mutation is a cancer-preventing operation for a high-risk population. For this series, jejunal pouch reconstruction was performed with encouragingly low postoperative morbidity, weight loss, and good subjective function.

CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment.

Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of CDH1, the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because CDH1 germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of CDH1 mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes "invasive" in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for CDH1 mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, CDH1 germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of CDH1 mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with CDH1 germline mutations and future research directions are also discussed.

[Hereditary gastric and pancreatic cancer]. / Hereditäres Magen- und Pankreaskarzinom.

Most cases of gastric and pancreatic cancer are sporadic, but familial clustering can be observed in approximately 10% of cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and two syndromes have been characterized: hereditary diffuse gastric cancer (HDGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Gastric and pancreatic cancer can develop in the setting of other hereditary cancer syndromes, such as hereditary breast and ovarian cancer syndrome (HBOC), Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis (FAP), or various hamartomatous polyposis syndromes, including juvenile polyposis and Peutz-Jeghers syndrome. Patients with hereditary pancreatitis carry an increased risk of cancer (40-55%).

[Precursors of gastric cancer : Dysplasia and adenoma]. / Vorstufen des Magenkarzinoms : Dysplasie und Adenom.

Gastric cancer develops from preneoplastic and early neoplastic precursor lesions. In particular, the intestinal type according to the Lauren classification is driven by chronic inflammation and progresses via a chronic gastritis - atrophy/metaplasia - dysplasia - carcinoma sequence. Staging of the extent of atrophy (OLGA) or intestinal metaplasia (OLGIM) enables risk stratification and determines follow-up investigations according to the management of precancerous conditions and lesions in the stomach (MAPS) international guidelines. True adenomatous lesions are relatively rare in the stomach. Three major types need to be considered: the intestinal type (tubular, tubulovillous and villous), the foveolar type (with superficial gastric differentiation) and the pyloric gland adenoma (with deep gastric differentiation). The intestinal type is the most common and needs to be differentiated from nonneoplastic polypoid regenerative hyperplasia, but also from well-differentiated tubular adenocarcinoma.

Cancer Worry, Perceived Risk and Cancer Screening in First-Degree Relatives of Patients with Familial Gastric Cancer.

Currently, there is a lack of evidence evaluating the psychological impact of cancer-related risk perception and worry in individuals at high risk for gastric cancer. We examined the relationships between perceived risk, cancer worry and screening behaviors among first-degree relatives (FDRs) of patients with familial gastric cancer. FDRs of patients diagnosed with familial gastric cancer with a non-informative genetic analysis were identified and contacted. Participants completed a telephone interview that assessed socio-demographic information, cancer risk perception, cancer worry, impact of worry on daily functioning, and screening behaviors. Twenty-five FDRs completed the telephone interview. Participants reported high levels of comparative and absolute cancer risk perception, with an average perceived lifetime risk of 54 %. On the other hand, cancer-related worry scores were low, with a significant minority (12 %) experiencing high levels of worry. Study participants exhibited high levels of confidence (median = 70 %) in the effectiveness of screening at detecting a curable cancer. Participants that had undergone screening in the past showed significantly lower levels of cancer-related worry compared to those that had never undergone screening. In conclusion, individuals at high-risk for gastric cancer perceived a very high personal risk of cancer, but reported low levels of cancer worry. This paradoxical result may be attributed to participants' high levels of confidence in the effectiveness of screening. These findings highlight the importance for clinicians to discuss realistic risk appraisals and expectations towards screening with unaffected members of families at risk for gastric cancer, in an effort to help mitigate anxiety and help with coping.

Prevalence of deleterious ATM germline mutations in gastric cancer patients.

Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.

Comparative prognosis efficacy between total laparoscopic gastrectomy and ordinary gastric cancer for familial gastric cancer / 实用肿瘤学杂志

Objective To compare the prognosis efficacy between total laparoscopic gastrectomy and or-dinary gastric cancer for familial gastric cancer.Methods The selected 60 patients with ordinary gastric cancer from August 2012 to 2014 in our hospital as the control group,the same period in familial gastric cancer of 40 pa-tients were chosen as control group.All patients were performed by total laparoscopic gastrectomy.Results The operative time,blood loss,postoperative discharge time compared in the two groups were showed no significant differences.However,the postoperative hospital stayed in the observation group and the number of lymph nodes were significantly longer more than the control group( P<0.001) .The postoperative pulmonary infection,intesti-nal obstruction,abdominal infection,anastomotic leakage,anastomotic bleeding and other complications in the ob-servation group were significantly lower than in the control group( P<0.001) .After the investigation,the dyspha-gia,pain,anxiety,physical appearance,dry mouth scores in the observation group were significantly higher(P<0. 001).Conclusion Familial gastric cancer has unique clinical and pathological features,Compared to ordinary stomach,the total laparoscopic gastrectomy treatment of familial gastric cancer need more lymph nodes dissection, it can cause more complications,it has some impacts on the quality of life for patients.

Hereditary diffuse gastric cancer - pathophysiology and clinical management.

Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas.

Analysis of clinical and pathological features of familial gastric cancer / 中国现代普通外科进展

Objective:To explore the clinical and pathological features of familial gastric cancer, and to get the early discovery and early treatment of it.Methods:Two kindreds of familial gastric cancer were followed up and their clinical and pathological features were analyzed.Results:Six patients with gastric cancer were found in the 2 kindreds.Autosomal dominant inheritance was observed in these cases.clinical and pathological features of familial gastric cancer were showed according to the document analysis:early onset;poor prognosis;patients suffer simultaneous or metachronous carcinoma;CDH1 germline mutation carriers had higher penetrance;pathologically, tumors are mostly diffuse infiltrative type with lower differentiated degree and earlier metastasis to lymphnodes;in one kindred,the sites of the lesions were relatively consistent.Conclusion:Familial gastric cancer has particular clinical and pathological features:early onset;poor prognosis;patients suffer simultaneous or metachronous carcinoma;CDH1 germline mutation carriers have higher penetrance; pathologically,tumors are mostly diffuse infiltrative type with lower differentiated degree and earlier metastasis to lymphnodes.