Annie On On Chan

BRAF Mutations in Aberrant Crypt Foci and Hyperplastic Polyposis

Patients with hyperplastic polyposis have multiple hyperplastic polyps (HPs) and increased risk of colorectal carcinomas. Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesions in colorectal carcinogenesis. We evaluated BRAF mutations by DNA sequencing in 53 ACF from patients with sporadic colorectal carcinomas and familial adenomatous polyposis, in 18 sporadic HPs from patients with resected colorectal cancer, and in 70 HPs, 4 serrated adenomas, 3 admixed hyperplastic-adenomatous polyps, 10 tubular adenomas, and 6 carcinomas from 17 patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status was compared with clinicopathological features and other genetic alterations by marginal logistic regression. BRAF mutation was present in only 2% of ACF and 6% of sporadic HPs. In contrast, BRAF mutation was present in 43% of HPs (P = 0.01 versus sporadic HPs), 75% of serrated adenomas, 33% of admixed hyperplastic-adenomatous polyps, 30% of tubular adenomas, and 33% of carcinomas from patients with multiple/large HPs and/or hyperplastic polyposis. BRAF mutation status in patients with multiple/large HPs and/or hyperplastic polyposis correlated with HPs from the same patient (odds ratio, 5.8; P = 0.0002) but associated with younger age (odds ratio, 0.83; P = 0.006 compared to older age), with a large HP (odds ratio, 22.5; P = 0.01 compared with patients with multiple HPs), with location of HPs in the right colon (odds ratio, 3.0; P = 0.03), and with methylation of the p16 gene and the MINT31 locus [odds ratio, 12.2 (P = 0.0001) and 4.4 (P = 0.02), respectively]. Our study shows that BRAF mutation status is heterogeneous among patients with multiple/large HPs and/or hyperplastic polyposis, suggesting differences in pathogenesis of HPs that indicate subsets within this phenotype.

Helicobacter pylori induces promoter methylation of E‐cadherin via interleukin‐1β activation of nitric oxide production in gastric cancer cells

Helicobacter pylori infection causes gastric mucosal inflammatory responses, resulting in up‐regulation of interleukin‐1β (IL‐1β) and overproduction of mutagenic nitric oxide (NO). The authors previously demonstrated that IL‐1β plays an important role in H. pylori‐induced E‐cadherin (E‐cad) methylation. Here, they extend the study to investigate the downstream effect of IL‐1β on H. pylori‐induced gastric inflammation and aberrant DNA methylation.

E-cadherin promoter hypermethylation induced by interleukin-1β treatment or H. pylori infection in human gastric cancer cell lines

Interleukin-1beta is up-regulated in the presence of Helicobacter pylori infection. H. pylori infection was associated with E-cadherin methylation. In this study, we examined if IL-1beta could induce promoter methylation of E-cadherin in human gastric cancer cell lines TMK-1, MKN-74 and MKN-7. Cells were treated with IL-1beta (0.025, 0.1, 0.25, 1.0, 2.5 ng/mL) for 6, 12 and 24h. Methylation status was determined by MSP and sequencing. The effects of IL-1beta or H.pylori on the cells, and after blockade with interleukin-1 receptor antagonist (IL-1ra) were tested. Promoter methylation of E-cadherin was induced in all three cells treated with IL-1beta or co-cultured with H. pylori. Treatment of IL-1ra could reverse the phenomena. Our study indicated that IL-1beta is an important step in mediating E-cadherin methylation.

Association between Helicobacter pylori infection and interleukin 1β polymorphism predispose to CpG island methylation in gastric cancer

Interleukin1β (IL1β) is upregulated in the presence of Helicobacter pylori infection.1 IL1β polymorphisms with T/T and T/C genotypes enhance IL1β production, and are associated with an increased risk of H pylori -induced hypochlorhydria2 and gastric cancer.3 The relationship between H pylori and CpG island methylation has been repeatedly reported.4–6 It has been reported that IL1β can modulate CpG island methylation through activation of DNA methyltransferase and hence repress gene expression.7 We therefore hypothesised that patients with H pylori infection and IL1 polymorphism, by the production of IL1β, are predisposed to gastric cancer development through the CpG island methylation pathway. We obtained surgical specimens and their corresponding peripheral blood from 98 consecutive patients with gastric cancer admitted to Queen Mary Hospital, Hong Kong. This study was approved by the ethics committee. The …

CpG Island Methylation in Precursors of Gastrointestinal Malignancies

Gastrointestinal malignancies account for about 20% of all cancers worldwide. It is widely accepted that cancer evolves through several stepwise morphological stages such as the adenoma-carcinoma and hyperplastic polyp-serrated adenoma-carcinoma sequences in colorectal cancers, and the metaplasia-dysplasia-carcinoma sequences in esophageal and gastric cancers. The morphological progression is associated with the accumulation of multiple genetic and epigenetic events. It is now recognized that epigenetic silencing of gene expression by CpG island methylation is an important alternative mechanism of inactivating tumor suppressor genes. Inflammatory conditions of the gastrointestinal and pancreaticobiliary tracts and liver such as Barrett esophagus, Helicobacter pylori gastritis, inflammatory bowel disease and viral hepatitis, are associated with increased frequency of malignancies and CpG methylation. In addition, CpG methylation is present in aberrant crypt foci and pancreatic intraepithelial neoplasia that are considered putative precursors of colon and pancreatic carcinomas, respectively. Understanding of these early genetic and epigenetic changes allows for the discoveries of potential screening, monitoring and therapeutic strategies. Targeting of the epigenetic changes that occur before the development of frank malignancy offers a potential chemopreventive strategy.

Characterization of interleukin-1β in Helicobacter pylori-induced gastric inflammation and DNA methylation in interleukin-1 receptor type 1 knockout (IL-1R1-/-) mice

Helicobacter pylori infection induced interleukin-1β (IL-1β) production and is associated with aberrant DNA methylation and gastric diseases. Here, we investigated the role of IL-1β in H. pylori-induced gastric inflammation and DNA methylation using IL-1 receptor type 1 knockout (IL-1R1(-/-)) mice, and compared the therapeutic efficacy of antimicrobial therapy with IL-1 receptor antagonist (IL-1ra). IL-1R1(-/-) and wild-type (WT) mice were infected with H. pylori for 16, 24 and 32 weeks. Infected WT mice at 24 weeks were given either antimicrobial therapy or IL-1ra. Comparing to the IL-1R1(-/-) mice, infected WT mice with functional IL-1β signaling had higher gastritis scores, higher IL-1β and iNOS mRNA expression, higher nitric oxide (NO) production and increased frequency of E-cadherin (E-cad) methylation at all the time points analyzed. IL-1β release was significantly elevated in infected WT mice than normal controls at 16 weeks post-infection (p<0.005). Treatment of infected mice with antimicrobial therapy and IL-1ra significantly reduced the degree of gastritis (p<0.005; p<0.05, respectively), iNOS expression (p<0.0001; p<0.01, respectively) and NO production (both p<0.001) compared with untreated controls. Mice receiving antimicrobial therapy had significantly lower IL-1β expression than untreated controls (p<0.0001). Both treatments reduced the incidence of E-cad methylation in infected mice compared with controls, however, no statistical significance was observed. There was no significant alteration of total DNA methyltransferase (DNMT) activity. These results demonstrated that IL-1β played a crucial role in H. pylori-induced gastric inflammation and DNA methylation. H. pylori eradication and IL-1ra administration could ameliorate inflammatory stress.

An Inverse Correlation between Interleukin-6 and Select Gene Promoter Methylation in Patients with Gastric Cancer

Background: Both serum IL-6 levels and CpG island methylation have been shown to have prognostic significance in gastric cancer, it was suggested that an important link existed between IL-6 and methylation of cancers. Aim: To investigate the prognostic value of IL-6 serum level and the association between serum IL-6 levels and CpG island methylation at p16, DAPK, MGMT and E-cadherin in patients with gastric cancer. Patients and Methods: Methylation status was assessed by MSP in 75 surgical specimens of gastric adenocarcinoma. IL-6 serum levels were measured by chemiluminescent enzyme immunoassay (CLEIA). Results: Methylation of p16, DAPK, MGMT, and E-cadherin were present in 53, 48, 32, and 59% of patients. Patients with tumors methylated at p16 and DAPK had lower serum levels of IL-6 compared to unmethylated tumors (1.8 vs. 4.8 pg/ml, p = 0.01 for p16; 1.5 vs. 6.2 pg/ml, p = 0.0001 for DAPK). But there was no difference with MGMT and E-cadherin methylation status. Serum IL-6 levels were also associated with TNM stage (p = 0.001), depth of tumor invasion (p = 0.002), lymphatic invasion (p = 0.01), vascular invasion (p = 0.008), metastasis (p = 0.002) and signet cell histology (p = 0.001). Conclusion: IL-6 is of prognostic value for patients of gastric cancer. Low serum IL-6 levels were associated with p16 or DAPK gene methylation in patients with gastric cancer.

Patients with functional constipation do not have increased prevalence of colorectal cancer precursors

It has always been a controversial subject whether patients with functional constipation have a higher risk of developing colorectal cancer. Watanabe et al 1 showed an increase in relative risk (RR) 1.31 of colorectal cancer in those with constipation.1 Roberts et al 2 showed an association with >twofold risk of colon cancer (OR 2.36) adjusted for age, race, sex and relevant confounders.2 On the other hand, both studies by Dukas et al 3 and Kune et al ,4 after adjusting for age, sex and other risk factors showed no increase in risk. Colorectal cancer develops through the adenoma–carcinoma sequence.5 Thus, we aimed to compare the prevalence of colorectal adenomas in patients with long-standing functional constipation to an age, sex and …

A patient with long-standing iron-deficient anemia

Background A 36-year-old Chinese woman presented with cutaneous lupus and was incidentally found to have iron-deficient anemia. She had a history of iron-deficient anemia 13 years previously, for which extensive investigations were carried out; the results of which were all normal. The patient also had pulmonary tuberculosis at that time, for which she received a full course of treatment. She required periodic blood transfusions and iron supplements to maintain her hemoglobin levels. She was subsequently discharged to a family clinic for follow-up until the current presentation.Investigations Upper endoscopy, colonoscopy, barium meal follow-through, small-bowel enema, 99mTc-labeled red-cell scan and double-balloon enteroscopy.Diagnosis Iron-deficient anemia due to obscure gastrointestinal bleeding caused by two small-bowel hemangiomas.Management Laparoscopic surgery.

Coping strategies, illness perception, anxiety, and depression of patients with idiopathic constipation: A population-based study

BACKGROUND Functional constipation has important psychological elements. AIM To investigate the prevalence of functional constipation in an Asian population, and the interplay among functional constipation, anxiety/depression, perception and coping strategies. METHODS An interview of 3282 patients was made by telephone survey. Constipation was diagnosed by Rome II criteria. Coping ability and anxiety/depression were assessed by validated questionnaires. RESULTS Fourteen percent of the interviewees had constipation. Anxiety and depression scores were higher in constipated than in healthy subjects (P < 0.0001 and < 0.0001), and in female than male patients (P = 0.02 and < 0.0001). Patients who were aware of their symptoms perceived greater impact on their lives (P < 0.001). Frequent use of coping strategies associated with lower anxiety scores (P < 0.0001). Female were more frequently aware of the symptoms (P = 0.004), less frequently used coping strategies (P = 0.008). Regression analysis showed that female and high anxiety level were the independent factors for predicting the perception of constipation, whereas anxiety was the only independent factor for predicting the use of coping strategies. CONCLUSION Constipation associated with anxiety and depression is prevalent in the general Asian population. Female sex and anxiety are important aetiological factors in constipation, affecting perception and the use of coping strategies.