BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer

Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 low-grade atypical GHPs (19.6%), 7 high-grade atypical GHPs (6.9%), and 5 intramucosal cancer samples (4.9%). GHP atypia was more common in the elderly and increased with increasing polyp size. In particular, polyps larger than 1 cm were associated with a higher grade and cancer. Furthermore, mucus production decreased with increasing atypia. Although no correlation was found between atypia and Helicobacter pylori infection or intestinal metaplasia, enhanced proliferative ability (Ki-67) did correlate with atypia, as did nuclear 8-hydroxy-2’-deoxyguanosine levels. Interestingly, 4-hydroxynonenal levels in granulation tissue and the area ratio of granulation tissue within polyps also correlated with GHP atypia. In five cases of HPAGC, three cases exhibited caudal type homeobox transcription factor (CDX2)-positive cells and a mixed mucin phenotype, which is considered to be related to H. pylori infection. By contrast, two cases were CDX2 negative, with a gastric mucin phenotype, and H. pylori infection was not observed in the tumor or the surrounding mucosa. In these cases, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (V600E) was detected. All cancer samples showed high stemness and p53 protein accumulation, but no KRAS mutations. The molecular and phenotypic characteristics of the cases characterized by BRAF mutations may represent a novel subtype of HPAGC, reflecting a conserved pathway to oncogenesis that does not involve H. pylori infection. These findings are worthy of further investigation in a large-scale study with a substantial cohort of HPAGC patients to establish their clinical significance.

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Comparative Genomics ofH. pyloriand Non-PyloriHelicobacterSpecies to Identify New Regions Associated with Its Pathogenicity and Adaptability

BioMed Research International ◽

10.1155/2016/6106029 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 8

Author(s):

De-Min Cao ◽

Qun-Feng Lu ◽

Song-Bo Li ◽

Ju-Ping Wang ◽

Yu-Li Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Functional Annotation ◽

Human Population ◽

Large Scale ◽

Bacterial Species ◽

Human Beings ◽

Gram Negative ◽

Protein Protein Interaction ◽

H Pylori ◽

Cooperation Relationship

The genusHelicobacteris a group of Gram-negative, helical-shaped pathogens consisting of at least 36 bacterial species.Helicobacter pylori(H. pylori), infecting more than 50% of the human population, is considered as the major cause of gastritis, peptic ulcer, and gastric cancer. However, the genetic underpinnings ofH. pylorithat are responsible for its large scale epidemic and gastrointestinal environment adaption within human beings remain unclear. Core-pan genome analysis was performed among 75 representativeH. pyloriand 24 non-pylori Helicobactergenomes. There were 1173 conserved protein families ofH. pyloriand 673 of all 99Helicobactergenus strains. We found 79 genome unique regions, a total of 202,359bp, shared by at least 80% of theH. pyloribut lacked in non-pylori Helicobacterspecies. The operons, genes, and sRNAs within theH. pyloriunique regions were considered as potential ones associated with its pathogenicity and adaptability, and the relativity among them has been partially confirmed by functional annotation analysis. However, functions of at least 54 genes and 10 sRNAs were still unclear. Our analysis of protein-protein interaction showed that 30 genes within them may have the cooperation relationship.

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p53 Immunoexpression in Carcinomas Arising in Pleomorphic Adenoma

International Journal of Surgical Pathology ◽

10.1177/106689699604030405 ◽

1996 ◽

Vol 3 (4) ◽

pp. 257-262 ◽

Cited By ~ 5

Author(s):

Joaninha Costa Rosa ◽

Isabel Fonseca ◽

Ana Félix ◽

Jorge Soares

Keyword(s):

Pleomorphic Adenoma ◽

P53 Protein ◽

P53 Gene ◽

Tumor Grade ◽

Undifferentiated Carcinoma ◽

Protein Accumulation ◽

Low Grade ◽

Histologic Type ◽

Epithelial Myoepithelial Carcinoma ◽

Invasive Carcinomas

p53 protein immunoexpression was evaluated in 17 invasive carcinomas arising in pleomorphic adenoma and correlated with the histologic type and tumor grade. Ten tumors had one malignant histologic component: adenocarcinoma NOS (not otherwise specified) (five), undifferentiated carcinoma (two), malignant myoepithelioma (one), epithelial-myoepithelial carcinoma (one), and malignant oncocytoma (one). In the remaining cases, there was a coexistence of areas of adenocarcinoma (seven), adenosquamous (two), epithelial-myoepithelial (two), adenoid cystic (two), undifferentiated carcinoma (one), and low-grade polymorphous adenocarcinoma (one). p53 positivity was found within adenocarcinoma NOS (three) and adenosquamous carcinoma (two) components of four cases. Tumor areas showing low-grade histology, either mono- or bidifferentiated carcinomas, were always negative in this series, in keeping with previous observations on primary neoplasms of the same histologic type. The benign component of the neoplasms was also found to be consistently negative. The results point to a preferential association of the p53 gene dysfunction and its protein accumulation with the malignant transformation of pleomorphic adenomas into salivary adenocarcinomas with features of high-grade malignancy.

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Predictors for development of complete and incomplete intestinal metaplasia (IM) associated with H. pylori infection: A large-scale study from low prevalence area of gastric cancer (IM-HP trial)

PLoS ONE ◽

10.1371/journal.pone.0239434 ◽

2020 ◽

Vol 15 (10) ◽

pp. e0239434

Author(s):

Natsuda Aumpan ◽

Ratha-Korn Vilaichone ◽

Pongjarat Nunanan ◽

Soonthorn Chonprasertsuk ◽

Sith Siramolpiwat ◽

...

Keyword(s):

Gastric Cancer ◽

Intestinal Metaplasia ◽

Large Scale ◽

Large Scale Study ◽

H Pylori ◽

Low Prevalence

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Strategies for Prevention of Gastric Cancer: Progress from Mass Eradication Trials

Digestive Diseases ◽

10.1159/000445229 ◽

2016 ◽

Vol 34 (5) ◽

pp. 500-504 ◽

Cited By ~ 5

Author(s):

Kentaro Sugano

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Large Scale ◽

Eradication Therapy ◽

Subsequent Development ◽

International Agency ◽

Preventive Strategy ◽

Implementation Phase ◽

The Government ◽

H Pylori

Background:Helicobacter pylori infection is the cause of the majority of gastric cancer. Meta-analyses on several interventional trials, irrespective of the target population, unanimously demonstrated the benefit of eradication therapy in reducing the occurrence of gastric cancer. Based on the evidence for the preventive effects on gastric cancer by eradication therapy in the general population, the International Agency for Research on Cancer advocated eradication of H. pylori as the primary preventive strategy for gastric cancer. Consensus reports on H. pylori gastritis by experts also recommended eradication of H. pylori as the strategy for prevention of gastric cancer. Key Messages:H. pylori is responsible for the majority of gastric cancer. As the eradication of the infection has been shown to reduce subsequent development of gastric cancer, a number of large-scale controlled trials involving a large number of subjects are currently underway in various countries to further verify the feasibility and effects of H. pylori eradication on gastric cancer prevention. However, such studies might be considered unethical as we already knew that the criminal role of H. pylori in gastric carcinogenesis. In Japan, rather than conducting clinical trials, the government adopted insurance coverage for H. pylori gastritis irrespective of symptoms. This policy brought about a massive surge in eradication therapy, which will ensue in a drastic reduction in the prevalence of H. pylori by 2030 as well as gastric cancer. Conclusions: Primary prevention of gastric cancer is now moving into implementation phase in Japan and will be spreading in other counties where long-term clinical trials have started.

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A study on the effect of Helicobacter pylori infection on p53 expression in gastric cancer and gastritis tissues

The Journal of Infection in Developing Countries ◽

10.3855/jidc.2993 ◽

2013 ◽

Vol 7 (09) ◽

pp. 651-657 ◽

Cited By ~ 9

Author(s):

Barik A Salih ◽

Zuhal Gucin ◽

Nizamettin Bayyurt

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

P53 Protein ◽

Immunohistochemical Analysis ◽

Intestinal Type ◽

Diffuse Type ◽

P53 Expression ◽

Normal Tissues ◽

Genotype Frequencies ◽

H Pylori

Introduction: Helicobacter pylori cause damage to gastric epithelial cells and alterations in the p53 gene that lead to cancer development. This study aimed to determine the correlation of p53 expression with H. pylori using immunohistochemistry, RFLP-PCR, and histopathology. Methodology: Gastric biopsy samples from gastric cancer (GC) (n = 54) and gastritis (n = 31) patients were examined for histopathological changes and expression of p53 protein by immunohistochemistry. Results: Immunohistochemical analysis of p53 protein expression in H. pylori-positive GC sections showed an average of 44.3% positive cells in tumors and 6.9% in normal tissues, as compared to 16.4% and 4.4% in H. pylori-negative sections. P53 expression showed significant association with H. pylori (P = 0.005), invasion depth (P = 0.029) and inflammation reaction (P = 0.008). In gastritis sections, no difference in the average p53 staining in H. pylori-positive or -negative sections was seen. PCR-RFLP results also showed no difference in genotype frequencies of p53 in H. pylori-positive or -negative gastritis sections. Histopathology study of H. pylori-positive GC sections showed that 97.2% were the intestinal type and 2.8% the diffuse type, while in H. pylori-negative sections 35.2% were the intestinal type and 64.8% the diffuse type. Biopsy sections from H. pylori-positive gastritis patients revealed more severe inflammation than those of H. pylori-negative patients. Conclusion: Our results show that H. pylori infection affects p53 expression in GC. The average p53 expression was significantly higher in tumor than in normal tissues. In gastritis sections p53 expression was significantly associated with H. pylori.

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Detection of Early Gastric Cancer after Helicobacter pylori Eradication

Digestion ◽

10.1159/000519838 ◽

2021 ◽

pp. 1-8

Author(s):

Satoki Shichijo ◽

Noriya Uedo ◽

Tomoki Michida

Keyword(s):

Risk Factors ◽

Gastric Cancer ◽

Helicobacter Pylori ◽

Early Gastric Cancer ◽

Eradication Therapy ◽

Low Grade ◽

Gastric Cancers ◽

Risk Patients ◽

Linked Color Imaging ◽

H Pylori

Background: Based on evidence that Helicobacter pylori eradication reduces the development of gastric cancer and other diseases such as peptic ulcer, eradication therapy has prevailed. However, gastric cancer can develop even after successful eradication. Summary: In this review article, we searched for studies that identified the characteristics of primary and metachronous gastric cancers after H. pylori eradication, the risk factors for the development of these cancers after successful H. pylori eradication, and whether image-enhanced endoscopy is useful for diagnosing gastric cancer after eradication. A gastritis-like appearance is seen as a characteristic endoscopic finding, which corresponds to an epithelium with low-grade atypia – also known as nonneoplastic epithelium – covering the surface of the cancerous glands. This finding may make endoscopic detection of early gastric cancer difficult after H. pylori eradication. Similar risk factors, such as the male sex, endoscopic atrophy, histologic intestinal metaplasia, and late eradication, have been reported as predictors for the development of both primary and metachronous gastric cancers. Image-enhanced endoscopy, such as linked color imaging, may be useful for the detection and risk stratification of gastric cancer after eradication. Key Messages: Based on these findings, we believe that effective surveillance of high-risk patients leads to early detection of gastric cancer in the era of H. pylori eradication.

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Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients

Gut ◽

10.1136/gutjnl-2017-314600 ◽

2018 ◽

Vol 68 (1) ◽

pp. 11-17 ◽

Cited By ~ 46

Author(s):

Massimo Rugge ◽

Alberto Meggio ◽

Cecilia Pravadelli ◽

Mattia Barbareschi ◽

Matteo Fassan ◽

...

Keyword(s):

Gastric Cancer ◽

Prospective Study ◽

Stage Iv ◽

Intraepithelial Neoplasia ◽

Stage Iii ◽

Low Grade ◽

Neoplastic Progression ◽

Gastric Epithelial Neoplasia ◽

Neoplastic Lesions ◽

H Pylori

ObjectiveOperative link on gastritis assessment (OLGA) staging for gastritis ranks the risk for gastric cancer (GC) in progressive stages (0–IV). This prospective study aimed at quantifying the cancer risk associated with each gastritis stage.DesignA cohort of 1755 consecutive patients with dyspepsia underwent initial (T-0) oesophagogastroduodenoscopy with mapped gastric biopsies, OLGA staging and assessment of Helicobacter pylori infection. Patients were followed for 55 months (median); patients with stages II III and IV underwent a second endoscopy/restaging (T-1), and those with stages 0 and I were followed clinically and through in-depth clinical and record checking. Endpoints were OLGA stage at T-1 and development of gastric epithelial neoplasia.ResultsAt T-0, 77.6% of patients had stage 0, 14.4% stage I, 5.1% stage II, 2.1% stage III and 0.85% stage IV. H. pylori infection was detected in 603 patients at T-0 and successfully eradicated in 602 of them; 220 had a documented history of H. pylori eradication; and 932 were H. pylori naïve-negative. Incident neoplastic lesions (prevalence=0.4%; low-grade intraepithelial neoplasia (IEN)=4; high-grade IEN=1; GC=2) developed exclusively in patients with stages III–IV. The risk for epithelial neoplasia was null in patients at stages 0, I and II (95% CI 0 to 0.4), 36.5 per 1000 person-years in patients at stage III (95% CI 13.7 to 97.4) and 63.1 per 1000 person-years in patients at stage IV (95% CI 20.3 to 195.6).ConclusionsThis prospective study confirms that OLGA staging reliably predicts the risk for development of gastric epithelial neoplasia. Although no neoplastic lesions arose in H. pylori-naïve patients, the H. pylori eradication in subjects with advanced stages (III–IV) did not abolish the risk for neoplastic progression.

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Analysis of Risk Factors of Gastric Low-Grade Intraepithelial Neoplasia in Asymptomatic Subjects Undergoing Physical Examination

Gastroenterology Research and Practice ◽

10.1155/2020/7907195 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Yingling Liu ◽

Yuli Cai ◽

Si Chen ◽

Yawen Gou ◽

Qiaomin Wang ◽

...

Keyword(s):

Risk Factors ◽

Gastric Cancer ◽

Physical Examination ◽

Precancerous Lesion ◽

Intraepithelial Neoplasia ◽

Low Grade ◽

Early Screening ◽

History Of ◽

H Pylori ◽

Asymptomatic Subjects

Secondary prevention is an important strategy in gastric cancer. Low-grade intraepithelial neoplasia (LGIN) is the last stage of precancerous lesion, and its timely diagnosis can greatly improve the detection rate of early gastric cancer. We performed a prospective study to analyze the risk factors of gastric LGIN in asymptomatic subjects undergoing physical examination. A total of 3437 subjects were included in this study, and 2259 asymptomatic subjects were investigated from March 2015 to April 2018. Risk factors were evaluated, and the endoscopic features of LGIN and prognosis were described. The overall incidence of LGIN was 19.73% (678/3437), while the incidence of LGIN in the asymptomatic and symptomatic groups was 19.65% (444/2259) and 19.86% (234/1178), respectively (P=0.884). The rate of Helicobacter pylori infection in this physical examination population was 39.13% (35.8% asymptomatic group, 45.5% symptomatic group; P≤0.001). Risk factors including age, H. pylori infection, history of antibiotic misuse, and spicy and high-fat diet (all P<0.05) were further verified by multivariate analysis as independent risk factors. History of antibiotic misuse and H. pylori infection showed significant associations with LGIN (odds ratio OR=6.767, 95% confidence interval (CI) 3.873-11.825 and OR=3.803, 95% CI 3.009-4.808, respectively). The most common endoscopic classification of LGIN was erosive gastritis (50.78%), and the major endoscopic appearance was Paris IIa (flat with slight elevation located mostly in the antrum). During the mean follow-up period of 15.02 months, 49.4% of LGIN regressed, 0.61% of LGIN progressed, and 50% of LGIN remained unchanged. History of antibiotic misuse and H. pylori infection were predominant risk factors of LGIN in asymptomatic subjects, and those individuals should consider early screening for gastric cancer.

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Pepsinogen Test for the Evaluation of Precancerous Changes in Gastric Mucosa: a Population-Based Study

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.271.pep ◽

2018 ◽

Vol 27 (1) ◽

pp. 11-17 ◽

Cited By ~ 4

Author(s):

Olga Sjomina ◽

Jelizaveta Pavlova ◽

Ilva Daugule ◽

Pavel Janovic ◽

Ilze Kikuste ◽

...

Keyword(s):

Gastric Cancer ◽

Strong Association ◽

Test Group ◽

Population Based ◽

Upper Gastrointestinal Endoscopy ◽

Low Grade ◽

Repeated Testing ◽

Cross Sectional ◽

Population Based Study ◽

H Pylori

Aims: The aim of the study was to evaluate the rationale of blood pepsinogen (PG) testing in population based screening settings.Methods: Participants from a cross-sectional population-based study of cardiovascular risk factors in Latvia were invited to participate in the current study. Pepsinogen I and II were measured in blood samples taken during the initial study and at follow-up; upper gastrointestinal endoscopy was performed. There were three groups of patients: with moderately decreased (PG I< 70 ng/ml and PG I/PG II ratio < 3), with strongly decreased (PG I< 30 ng/ml and PG I/PG II ratio < 2), and with normal PG level. Biopsy with H. pylori detection was performed (updated Sydney system).Results: Results from 259 patients were analyzed. Pepsinogens were decreased in 133 (51.4%), H. pylori was positive in 177 (66.0%) cases. Mean age was significantly lower in patients with normal compared to strongly decreased PG level group (52.8 vs. 64.1 years, p<0.001). Prevalence of severe corpus atrophy was higher in the strongly decreased compared to the normal PG test group: 7.0% vs. 0%; the same tendency was noted in the distribution of OLGA stages III-IV – 10.5% and 0.0%, OLGIM stages III-IV – 3.5% and 0%, and low-grade dysplasia – 15.8% and 2.4% (p<0.05). Two cases of gastric cancer were found; both presented decreased PG levels. A strong association between H. pylori eradication and PG ratio dynamics was found (p<0.05).Conclusions: All high-risk lesions were found in the decreased PG test groups; two cancer cases were revealed.However, PG demonstrated low specificity and low value of repeated testing. The value of PG as a sole test for gastric cancer risk is limited.

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p53 abnormalities in splenic lymphoma with villous lymphocytes

Blood ◽

10.1182/blood.v97.11.3552 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3552-3558 ◽

Cited By ~ 65

Author(s):

Alicja M. Gruszka-Westwood ◽

Rifat A. Hamoudi ◽

Estella Matutes ◽

Esperanza Tuset ◽

Daniel Catovsky

Keyword(s):

Flow Cytometry ◽

Protein Expression ◽

Direct Sequencing ◽

P53 Protein ◽

Protein Accumulation ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

Kaplan Meier ◽

Splenic Lymphoma

The incidence and role of p53 abnormalities have not been reported in splenic lymphoma with villous lymphocytes (SLVL), the leukemic counterpart of splenic marginal zone lymphoma. Because p53 abnormalities correlate with progressive and refractory disease in cancer and isochromosome 17q has been described in SLVL, a low-grade lymphoma that behaves aggressively in a minority of patients, this study investigated p53 changes by molecular and immunophenotypic methods in samples from 59 patients. The p53 deletion was analyzed by fluorescence in situ hybridization, and p53 protein expression was assessed by immunocytochemistry in 35 of 59 cases and by flow cytometry in 20 of 35 patients. Ten patients (17%) had a monoallelic p53 loss, 3 (9%) of 35 nuclear protein expression by immunocytochemistry, and 2 (10%) of 20 by flow cytometry. Two patients had both deletion and protein expression. Direct sequencing of all p53 exons was used to delineate mutations in 9 of 11 patients with an identified abnormality. Mutations, both compromising p53 DNA binding, were identified in the 2 patients with deletion and protein accumulation. Kaplan-Meier analysis revealed a significantly worse survival for patients with p53 abnormalities. Although p53 abnormalities are infrequent in SLVL, they underlie a more aggressive disease course and poor prognosis.

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