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Variation in human genetic polymorphisms, their association with Helicobacter pylori acquisition and gastric cancer in a multi-ethnic country

Schmidt HM, Ha DM, Taylor EF, Kovach Z, Goh KL, Fock KM, et al.

J Gastroenterol Hepatol, 2011 Dec;26(12):1725-32.
PMID: 21649724 DOI: 10.1111/j.1440-1746.2011.06799.x

BACKGROUND AND AIM: The contribution of human genetic polymorphisms to Helicobacter pylori infection and gastric cancer (GC) development remains unclear due to geographic variation in the association between specific host genetic polymorphisms and GC. In the current study we investigated the association between polymorphisms related to immune and cancer-related pathways and H. pylori infection among the major ethnicities, Chinese, Malay and Indian, resident in Singapore and Malaysia as well as the association between these polymorphisms and GC development in ethnic Chinese patients.
METHODS: Thirty-four polymorphisms in 26 genes were typed by mass spectrometry in 422 patients undergoing endoscopy (162 Chinese, 113 Indian and 87 Malay controls and 60 Chinese GC cases). Patients were assessed for evidence of H. pylori infection. Odds ratios (OR) and confidence intervals (CI) were obtained using logistic regression models.
RESULT: The prevalence of 16 polymorphisms varied significantly among the ethnicities. In the Chinese subgroup, nominally significant associations were shown between (i) EBBR2+1963G (rs1801200) and H. pylori infection (per-allele OR: 0.48, 95% CI 0.23, 0.98, P = 0.04), (ii) PTGS2-1195G (rs689466) and an increased risk of GC on adjusting for H. pylori status (OR: 1.53, 95% CI 0.99, 2.37, P = 0.05), and (iii) IL1B-1473C (rs1143623) and a decreased risk of GC (OR: 0.64, 95% CI 0.41, 0.99, P = 0.05). Borderline significant associations were seen between IL2-330G (rs2069762) (OR 1.45, 95% CI 0.95, 2.15, P = 0.06) and IL13-1111T (rs1800925) (OR 0.65, 95% CI 0.42, 1.01, P = 0.06) and H. pylori infection.
CONCLUSION: These findings contribute to the understanding of the genetic variation between ethnicities, which may influence H. pylori susceptibility and the outcome of infection.

Matched MeSH terms: Stomach Neoplasms/genetics*
Fulltext Prevalence of HER2 Positivity and Its Clinicopathological Correlation in Locally Advanced/Metastatic Gastric Cancer Patients in Malaysia

Rajadurai P, Fatt HK, Ching FY

J Gastrointest Cancer, 2018 Jun;49(2):150-157.
PMID: 28124769 DOI: 10.1007/s12029-017-9921-1

PURPOSE: Human epidermal growth factor receptor 2 (Erbb2/HER2) overexpression, which was previously detected in invasive breast cancer, has now been implicated in advanced gastric cancer (GC) and gastroesophageal junction cancer (GEC). A study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic GC and GEC in Malaysia and to assess the impact of various demographic and clinical parameters on HER2 positivity.
METHODS: A total of 228 adult patients with GC or GEC were enrolled from Subang Jaya Medical Centre, Malaysia, for retrospective (210) and prospective study. All patients were subjected to the HER2 immunohistochemistry test using an FDA-approved, standardized test kit. Carcinomas scoring 2+ on immunohistochemistry were further tested with HER2 in situ hybridization (ISH) using an FDA-approved test kit.
RESULTS: The overall rate of HER2 positivity in the population studied was 24.6% (n = 56). The rate was significantly higher in men than in women (29.6 vs. 16.3%; p = 0.024). HER2 overexpression was significantly more common in diffuse type than in intestinal type of tumors (39.8 vs. 14.9%; p

Matched MeSH terms: Stomach Neoplasms/genetics*
Autophagy in Helicobacter pylori Infection and Related Gastric Cancer

Castaño-Rodríguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM

Helicobacter, 2015 Oct;20(5):353-69.
PMID: 25664588 DOI: 10.1111/hel.12211

Autophagy, a degradation pathway in which cytoplasmic content is engulfed and degraded by lysosomal hydrolases, plays a pivotal role in infection and inflammation. Given that defects in autophagy lead to increased susceptibility to infection, we investigated the role of autophagy in Helicobacter pylori-related gastric cancer (GC).

Matched MeSH terms: Stomach Neoplasms/genetics
Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer

Haron NH, Mohamad Hanif EA, Abdul Manaf MR, Yaakub JA, Harun R, Mohamed R, et al.

Asian Pac J Cancer Prev, 2019 Feb 26;20(2):509-517.
PMID: 30803214

Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method: A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.

Matched MeSH terms: Stomach Neoplasms/genetics*
Fulltext Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection

Ravishankar Ram M, Goh KL, Leow AH, Poh BH, Loke MF, Harrison R, et al.

PLoS One, 2015;10(11):e0141865.
PMID: 26559190 DOI: 10.1371/journal.pone.0141865

Helicobacter pylori (H. pylori) -induced gastric inflammation impacts the functions of leptin- and ghrelin-producing cells in the gastroduodenum. Inflammation resulting from H. pylori sensing via Toll-like receptors (TLRs) and the associated downstream signaling largely remain ambiguous. Here, we investigated the role of gut hormones, pro-inflammatory cytokines and single nucleotide polymorphisms (SNPs) associated with TLR 4p14 in H. pylori disease in 30 subjects with non-ulcer dyspepsia (NUD), 40 with peptic ulcer disease (PUD) and 15 with gastric cancer (GC) subjects positive and negative for H. pylori infection. The level of pro-inflammatory cytokines was directly proportional to the severity of gastritis, and disease status influenced the levels of gut hormones and pro-inflammatory cytokines. TLR-1 SNPs rs4833095 and TLR-10 SNPs rs10004195 and were directly associated with H. pylori disease, and were up-regulated in the presence of H. pylori in a genotype-independent manner. We concluded that TLR-1 rs4833095 and TLR10 rs10004195 confer susceptibility to development of gastroduodenal disease, especially GC in H.pylori disease.

Matched MeSH terms: Stomach Neoplasms/genetics*
Fulltext Gastric precancerous lesions are associated with gene variants in Helicobacter pylori-susceptible ethnic Malays

Maran S, Lee YY, Xu S, Rajab NS, Hasan N, Syed Abdul Aziz SH, et al.

World J Gastroenterol, 2013 Jun 21;19(23):3615-22.
PMID: 23801863 DOI: 10.3748/wjg.v19.i23.3615

To identify genes associated with gastric precancerous lesions in Helicobacter pylori (H. pylori)-susceptible ethnic Malays.

Matched MeSH terms: Stomach Neoplasms/genetics*
Fulltext Local ablation of gastric cancer by reconstituted apolipoprotein B lipoparticles carrying epigenetic drugs

Yang CL, Chao YJ, Wang HC, Hou YC, Chen CG, Chang CC, et al.

Nanomedicine, 2021 10;37:102450.
PMID: 34332115 DOI: 10.1016/j.nano.2021.102450

Epigenetic inhibitors have shown anticancer effects. Combination chemotherapy with epigenetic inhibitors has shown high effectiveness in gastric cancer clinical trials, but severe side effect and local progression are the causes of treatment failure. Therefore, we sought to develop an acidity-sensitive drug delivery system to release drugs locally to diminish unfavorable outcome of gastric cancer. In this study, we showed that, as compared with single agents, combination treatment with the demethylating agent 5'-aza-2'-deoxycytidine and HDAC inhibitors Trichostatin A or LBH589 decreased cell survival, blocked cell cycle by reducing number of S-phase cells and expression of cyclins, increased cell apoptosis by inducing expression of Bim and cleaved Caspase 3, and reexpressed tumor suppressor genes more effectively in MGCC3I cells. As a carrier, reconstituted apolipoprotein B lipoparticles (rABLs) could release drugs in acidic environments. Orally administrated embedded drugs not only showed inhibitory effects on gastric tumor growth in a syngeneic orthotopic mouse model, but also reduced the hepatic and renal toxicity. In conclusion, we have established rABL-based nanoparticles embedded epigenetic inhibitors for local treatment of gastric cancer, which have good therapeutic effects but do not cause severe side effects.

Matched MeSH terms: Stomach Neoplasms/genetics
Genetic polymorphisms in the Toll-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer

Castaño-Rodríguez N, Kaakoush NO, Pardo AL, Goh KL, Fock KM, Mitchell HM

Hum Immunol, 2014 Aug;75(8):808-15.
PMID: 24929142 DOI: 10.1016/j.humimm.2014.06.001

Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC.

Matched MeSH terms: Stomach Neoplasms/genetics*