A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer

Purpose Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position –1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the –1562 C/T polymorphism and the development and progression of gastric cancer.Methods The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied.Results Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each).Conclusions Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.     

Distinct single nucleotide polymorphism pattern at the <Emphasis Type="Italic">FUT2</Emphasis> promoter among human populations

Many single nucleotide polymorphisms (SNPs) have been identified in the coding region of the FUT2 locus, which encodes secretor type α(1,2)fucosyltransferase. In this study, we analyzed the sequence variations in the proximal promoter region of FUT2 in several human populations. In African populations, we found two SNPs with intermediate frequency that affected the promoter activity in vitro with a cell type-specific pattern. On the other hand, these two African SNPs were rarely detected outside Africa. Linkage disequilibria (LD) were observed between some haplotypes of the promoter and coding regions, although no characteristic promoter haplotype was linked with the se ⁴²⁸ allele of the coding region, which is estimated to be old. The present results suggest that the pattern of variation in the proximal promoter differs between Africans and non-Africans.     

Novel <Emphasis Type="Italic">hMSH</Emphasis>2, <Emphasis Type="Italic">hMSH</Emphasis>6 and <Emphasis Type="Italic">hMLH</Emphasis>1 gene mutations and microsatellite instability in sporadic colorectal cancer

Purpose To detect the hMSH2, hMSH6 and hMLH1 DNA mismatch repair gene mutations and microsatellite instability in somatic colorectal cancer.Patients and methods The mutations of hMSH2, hMSH6, and hMLH1 genes, including microsatellite instability of BAT-26, BAT-40, D2S123, D5S346 and D17S250 were analyzed in 31 patients with colorectal.Results The results revealed that eight cases (25.8%) harbored mutations in DNA mismatch repair genes. Of these, five novel mutations including I237V in exon 4 of hMSH2, ins T at codon 1196 in exon 7 of hMSH6, and ins G at codon 154 in exon 6, N158H in exon 6, and del A at codon 257 in exon 9 of hMLH1 were identified. Moreover, several intronic polymorphisms, including c–g transversion at IVS-1 nt211 + 9 of hMSH2, del T in poly T track at IVS-6 nt3559-5, ATCT duplicate in IVS-7 nt 3642 + 35 and t–g transversion at IVS-10 nt4080 + 185 of hMSH6 were demonstrated in these patients. In addition, seven cases (22.5%) exhibited microsatellite instability (MSI).Conclusion These results suggested that the inactivation of DNA mismatch repair genes and microsatellite instability may play a minor role in somatic colorectal cancer development.     

<Emphasis Type="Italic"> BAX</Emphasis> and <Emphasis Type="Italic">caspase-5</Emphasis> frameshift mutations and spontaneous apoptosis in colorectal cancer with microsatellite instability

Background and aims Hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic colorectal cancers are characterized by microsatellite instability (MSI) and inactivating frameshift mutations of target genes. Inactivation of BAX, caspase-5 (cas-5), and other genes coding for pro-apoptotic proteins might contribute to tumor progression by enhancing escape from apoptosis. The aim of this study was to further characterize the role of BAX and cas-5 inactivation for spontaneous apoptosis.Methods Twenty-five colorectal cancers with MSI were analyzed for frameshift mutations in the BAX (G)8 and cas-5 (A)10 tract by fluorescence PCR, cloning, and sequencing. The rate of spontaneous apoptosis was examined by in situ DNA nick end-labeling. The results were compared with 25 stage-matched microsatellite stable (MSS) colorectal cancers.Results In colorectal cancer with MSI frameshift mutations in BAX and cas-5 were present in 16 of 25 (64%) and in 12 of 25 (48%) tumors, respectively, whereas neither mutant BAX nor cas-5 alleles were detected in all stage-matched sporadic MSS colorectal cancer. Tumors with MSI showed a higher apoptotic rate than MSS tumors (2.5±1.0 vs. 2.1±0.7; p <0.05), whereas the presence of BAX or cas-5 frameshift mutations had only minor influence on this finding (2.4±1.1% and 2.5±0.9%, respectively).Conclusion Mismatch-repair deficiency itself is associated with increased spontaneous apoptosis, not further accelerated by either inactivating BAX or cas-5 frameshift mutations.This work was supported by grants from the Johann Wolfgang Goethe University Frankfurt a.M. (F15/01) and the Paul and Ursula Klein Foundation     

Establishment of thymoma-prone congenic rat strain,ACI.BUF/Mna-<Emphasis Type="Italic">Tsr1</Emphasis>/<Emphasis Type="Italic">Tsr1</Emphasis>

Purpose To confirm the presence of the susceptible gene for the thymoma development in the region that was assumed by the previous linkage study by Oyabu et al. (J Natl Cancer Inst 91:279–282, 1999), we tried to establish a congenic strain of rats. Methods Backcrossings between the BUF/Mna strain as a donor strain and the ACI/NMna strain as an inbred partner were repeated for 12 generations, examining whether rats had the thymoma development region, and then homozygous rats were yielded by mating among the heterozygotes. To detect the phenotypic expression, heterozygous ACI.BUF/Mna-Tsr1/+ (ACI-Tsr1/+) rats were generated by crossing female ACI.BUF/Mna-Tsr1/Tsr1 (ACI-Tsr1/Tsr1) rats with male ACI/NMna rats and were maintained for 24 months. Results These ACI-Tsr1/+ rats produced thymoma in 71%, showing a dominant trait. The thymomas were of the lymphocyte predominant type, as those developed in rats of the original BUF/Mna strain. Conclusions Thus, a new rat congenic strain, ACI-Tsr1/Tsr1, was established, revealing that thymoma develops in the dominant trait in ACI-Tsr1/+ rats.     

Low presence of <Emphasis Type="Italic">p53</Emphasis> abnormalities in <Emphasis Type="Italic">H. pylori</Emphasis>-infected gastric mucosa and in gastric adenocarcinoma

Background: Alterations of the p53 gene and/or its abnormal protein accumulation have been observed in gastric cancer and preneoplastic lesions. Our aim was to assess possible associations between different H. pylori strains and p53 abnormalities in patients with dyspepsia and with gastric cancer. Methods: Seventy-five dyspeptic patients and 40 patients with gastric adenocarcinoma entered the study. H. pylori status was determined by the rapid urease test, histology, and polymerase chain reaction (PCR) analysis. Overexpression of the p53 protein was evaluated by immunohistochemistry. Detection of p53 mutations was done by direct DNA sequencing. Results: Fifty-four of the 75 (72.0%) dyspeptic patients and 27 of the 40 (67.5%) gastric cancer patients showed H. pylori infection. Cytotoxin-associated gene (cagA)-positive strains were found in 31 of the 54 (58%) dyspeptic patients and in 25 of the 27 (92.6%) neoplastic patients. As regards vacA, s2 strains showed the highest prevalence among dyspeptic patients (24 of 54 patients; 44.4%), whereas s1 strains were more expressed among cancer patients (23 of 27; 85.2%). Among the dyspeptic patients, 1 patient with duodenal ulcer showed p53 overexpression. Three mutations were identified by DNA sequencing: one in a patient with normal endoscopic findings and two in patients suffering from gastritis. Among the neoplastic patients, 16 subjects (40%) showed p53 overexpression (9 had diffuse-type and 7 intestinal-type cancer). Four mutations (10%) occurred in patients with intestinal-type gastric cancer. No association between p53 abnormalities (overexpression/mutation) and H. pylori infection was found in either group of patients. Conclusions: These results lead us to hypothesize that H. pylori infection does not affect the p53 pattern in gastric mucosa. Moreover, mutations of the p53 gene do not seem to be a predominant event in gastric carcinogenesis, at least in our populations. Received: December 14, 2001 / Accepted: May 17, 2002 RID="*" ID="*"  These authors contributed equally to the work RID="*" ID="*"  These authors contributed equally to the work Acknowledgments. The authors would like to thank Mrs B. D'Attoma and Mrs P. Fiorente for their valuable technical assistance, and Mrs M.V.C. Pragnell, B.A., for her help in revising the English. Reprint requests to: A. Di Leo     

<Emphasis Type="Italic">Di</Emphasis>abetesintervention mit<Emphasis Type="Italic"> Ator</Emphasis>vastatin (DIATOR)

Zusammenfassung Statine haben bei der Prävention von vaskulären Ereignissen einen sehr hohen Stellenwert. Als Wirkmechanismus wird primär die Senkung des LDL-Cholesterins gesehen. In den letzten Jahren konnten zudem diverse immunmodulatorische Wirkungen nachgewiesen werden, die in dieser Übersichtsarbeit diskutiert werden. Diese neuen Erkenntnisse haben dazu geführt, dass vom Deutschen Diabeteszentrum eine multizentrische Interventionsstudie begonnen wurde, bei der die beim frisch manifesten Typ-1-Diabetes noch vorhandene residuelle Insulinproduktion durch eine Therapie mit Atorvastatin erhalten werden soll.     

Aberrant methylation of <Emphasis Type="Italic">SOCS-1</Emphasis> was observed in younger colorectal cancer patients

Background Recently, it was demonstrated that suppressor of cytokine signaling-1 (SOCS-1) was frequently silenced by methylation of its CpG island in human hepatocellular carcinoma (HCC). To define the role of SOCS-1 in the tumorigenic pathway of the colorectum, we examined the methylation of SOCS-1 in tumors of colorectal cancer patients.Methods We examined 74 colorectal cancer patients, using a methylation-specific polymerase chain reaction (PCR; MSP) for SOCS-1 CpG island in primary tumors.Results Aberrant methylation of the SOCS-1 CpG island was detected in 6 of the 74 (8%) colorectal cancer specimens. No corresponding normal colorectal tissues showed SOCS-1 methylation. We then analyzed the correlation between the clinicopathological features and SOCS-1 aberrant methylation and found that younger age was significantly related to SOCS-1 methylation (P = 0.048).Conclusions These findings suggested that SOCS-1 may act as a tumor suppressor in at least some colorectal cancers and that SOCS-1 methylation may be a particular phenomenon related to an early onset of colorectal cancer.     

<Emphasis Type="Italic">hSNF5</Emphasis><Emphasis Type="Italic">/INI1</Emphasis> mutation analysis in acute myeloid leukemia

Previous studies indicated that region 11.2 of the long arm of chromosome 22 (22q11.2) might be a locus encoding a tumor suppressor gene, since its deletion is a recurrent genetic characteristic of aggressive pediatric cancer. This region is found in the human immunodeficiency virus integrase interactor 1 (hSNF5/INI1) gene. To investigate whether the hSNF5/INI1 gene is involved in leukemogenesis, mutation analysis of the hSNF5/INI1 gene was performed in the present study using 5 hematopoietic cell lines, acute myeloid leukemia (AML) specimen and normal control. We found two single nucleotide polymorphisms at the hSNF5/INI1 gene in exon 4 and exon 9. The results of this study suggest that the hSNF5/INI1 gene does not play an important role in the leukemogenesis of AML.     

<Emphasis Type="Italic">T-</Emphasis>Scores and <Emphasis Type="Italic">Z</Emphasis>-Scores

Bone mineral density (BMD) can be measured by a variety of techniques at several skeletal sites. Once measured, the manufacturers’ software uses the BMD to calculate a T-score and/or Z-score. Both T-scores and Z-scores are derived by comparison to a reference population on a standard deviation scale. The recommended reference group for the T-score is a young gender-matched population at peak bone mass, while the Z-score should be derived from an age-matched reference population. T-scores and Z-scores are widely quoted in scientific publications on osteoporosis and BMD studies, and are the values used for DXA diagnostic criteria and current clinical guidelines for the management of osteoporosis. Errors in BMD measurement, differences in reference populations, and variations in calculation methods used, can all affect the actual T-score and Z-score value. Attempts to standardize these values have made considerable progress, but inconsistencies remain within and across BMD technologies. This can be a source of confusion for clinicians interpreting BMD results. A clear understanding of T-scores and Z-scores is essential for correct interpretation of BMD studies in clinical practice.     

Joint effects of HLA, <Emphasis Type="Italic">INS</Emphasis>, <Emphasis Type="Italic">PTPN22</Emphasis> and <Emphasis Type="Italic">CTLA4</Emphasis> genes on the risk of type 1 diabetes

Background/hypothesis HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. Methods We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, −DQA1 and −DQB1, the insulin gene (INS, −23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). Results The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene–gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). Conclusion Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

<Emphasis Type="Italic">GSTP1</Emphasis> and <Emphasis Type="Italic">MDR1</Emphasis> Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure. These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.     

Associations of <Emphasis Type="Italic">TIM</Emphasis>-<Emphasis Type="Italic">1</Emphasis> Genetic Polymorphisms with Asthma: A Meta-analysis

Purpose

Recently, the roles of TIM-1 genetic polymorphisms in asthma have been extensively studied, with conflicting results. Therefore, we performed the present meta-analysis to better assess potential associations of TIM-1 genetic polymorphisms with asthma.

Methods

Eligible articles were searched in PubMed, Medline, EMBASE, Google Scholar, and CNKI up to December 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between TIM-1 genetic polymorphisms and asthma.

Results

A total of 12 articles including 3120 asthma patients and 2825 control subjects were analyzed. The overall and subgroup analyses revealed that TIM-1-416G>C single nucleotide polymorphism was significantly associated with asthma for the Asian population in the codominant (G/G vs. G/C, p = 0.0003, OR 1.86, 95% CI 1.33–2.60) and dominant (G/G vs. G/C + C/C, p < 0.0001, OR 1.94, 95% CI 1.40–2.69) genetic models. Nevertheless, we failed to detect any significant associations between TIM-1-416G>C single nucleotide polymorphism and asthma in Caucasians. Additionally, according to our analyses, TIM-1 5383_5397 insertion/deletion polymorphism was not correlated with asthma in both Asians and Caucasians.

Conclusions

In conclusion, our findings suggest that TIM-1-416G>C single nucleotide polymorphism is associated with asthma susceptibility for the Asian ethnicity in certain genetic models. However, TIM-1 5383_5397 insertion/deletion polymorphism may not be correlated with the risk of asthma.

     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> CagA protein variation associated with gastric cancer in Asia

Recent molecular analysis has provided the pathological actions of CagA on gastric epithelial cells. CagA is injected into epithelial cells via the type IV secretion system and undergoes tyrosine phosphorylation in the cells. In addition, translocated CagA forms a physical complex with SHP-2. There are two major CagA subtypes; the East Asian and the Western type. The East Asian CagA protein possesses stronger SHP-2 binding activity than the Western CagA. The grades of inflammation, activity of gastritis, and atrophy are significantly higher in gastritis patients infected with the East Asian CagA-positive strain than in gastritis patients infected with the cagA-negative or Western CagA-positive strains. The prevalence of the East Asian CagA-positive strain is associated with the mortality rate of gastric cancer in Asia. Endemic circulation of H. pylori populations carrying biologically more active CagA proteins in East Asian countries, where the mortality rate of gastric cancer is among the highest in the world, may be involved in increasing the risk of gastric cancer in these populations.     

E-cadherin (<Emphasis Type="Italic">CDH1</Emphasis>) gene promoter polymorphism and the risk of colorectal cancer

Objective  

Published data on the relationship between E-cadherin (CDH1) gene promoter polymorphisms and colorectal cancer (CRC) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was carried out.     

Mutation Analysis of <Emphasis Type="Italic">SPINK1</Emphasis> and <Emphasis Type="Italic">CFTR</Emphasis> Gene in Korean Patients with Alcoholic Chronic Pancreatitis

Several genetic mutations have been reported to increase susceptibility to chronic pancreatitis. However, their roles in alcoholic chronic pancreatitis are controversial. We investigated the prevalence of SPINK1 N34S and new CFTR Q1352H mutations in alcoholic chronic pancreatitis in Korea. Forty-three patients with alcoholic chronic pancreatitis were enrolled and 35 healthy individuals served as controls. The SPINK1 N34S mutation was detected by the PCR-RFLP technique. The CFTR Q1352H mutation was examined with PCR direct sequencing. Mean age of chronic pancreatitis and control groups was 53.2 and 51.3 years, respectively. A SPINK1 N34S was detected as a heterozygote in one (2.4%) patient with alcoholic chronic pancreatitis and a heterozygote CFTR Q1352H was detected in one other patient. In the control population, neither SPINK1 nor CFTR mutation was detected. This study shows that SPINK1 N34S and CFTR Q1352H mutations are uncommon and do not play an important role in chronic alcoholic pancreatitis in Korea.