Low Expression of E-Cadherin and Cdh1 Variants Associated with Diffuse Gastric Cancer

ABSTRACT Background Reduced or null expression of E-cadherin protein is a frequent cause of diffuse gastric cancer (DGC). More than 50% of patients with DGC present somatic variants in CDH1 gene. Objectives The objectives of this study were to study E-cadherin expression and identify variants in the CDH1 gene in gastric tumors of patients with DGC. Methods We studied 18 Mexican DGC patients who attended a hospital of the Mexican Social Security Institute; E-cadherin expression was determined by immunohistochemistry, and variants were identified by Sanger sequencing in promoter and coding regions. Predictive analysis was performed using PolyPhen-2 and HOPE software. Results We found that 56% of DGC patients showed reduced expression of E-cadherin. All patients carried CDH1 variants; overall, 12 different CDH1 variants were identified. Predictive analysis revealed that the rs114265540 variant was probably damaging, with a value of 0.985, indicating a functional impact on the E-cadherin protein. Variants rs34939176 and rs33964119 were identified as risk factors for DGC (odds' ratios [OR] = 31.3, 95% CI 6.3-154.0, p < 0.001; OR = 6.1, 95% CI 2.0-19.0, p < 0.001, respectively) given their elevated frequency and by comparing it with those reported for MXL population in the 1000 Genomes Project database. Conclusions In this Mexican population, the percentage of diffuse gastric tumors with reduced expression of E-cadherin was similar to that reported in other populations. All gastric tumors of DGC patients studied had somatic CDH1 gene variants; however, the rs114265540, rs34939176, and rs33964119 variants were importantly related to DGC.

Association of CDH11 with Autism Spectrum Disorder Revealed by Matched-gene Co-expression Analysis and Mouse Behavioral Studies / 神经科学通报·英文版

A large number of putative risk genes for autism spectrum disorder (ASD) have been reported. The functions of most of these susceptibility genes in developing brains remain unknown, and causal relationships between their variation and autism traits have not been established. The aim of this study was to predict putative risk genes at the whole-genome level based on the analysis of gene co-expression with a group of high-confidence ASD risk genes (hcASDs). The results showed that three gene features - gene size, mRNA abundance, and guanine-cytosine content - affect the genome-wide co-expression profiles of hcASDs. To circumvent the interference of these features in gene co-expression analysis, we developed a method to determine whether a gene is significantly co-expressed with hcASDs by statistically comparing the co-expression profile of this gene with hcASDs to that of this gene with permuted gene sets of feature-matched genes. This method is referred to as "matched-gene co-expression analysis" (MGCA). With MGCA, we demonstrated the convergence in developmental expression profiles of hcASDs and improved the efficacy of risk gene prediction. The results of analysis of two recently-reported ASD candidate genes, CDH11 and CDH9, suggested the involvement of CDH11, but not CDH9, in ASD. Consistent with this prediction, behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autism-like behavioral alterations. This study highlights the power of MGCA in revealing ASD-associated genes and the potential role of CDH11 in ASD.

CRISPR/Cas9-mediated activation of CDH1 suppresses metastasis of breast cancer in rats

BACKGROUND Cancer is a life-threatening disease that affects approximately 18 million individuals worldwide. Breast cancer is the most common female neoplasm globally with more than 276,480 new cases of invasive breast cancer expected to be diagnosed in women in the U.S. alone in 2020. Genetic and epigenetic factors play role in the carcinogenesis and progression of this disease. In this study, MCF-7 adenocarcinoma cells were transfected with CRISPR/Cas9 plasmid to either knock out CDK11 or to activate CDH1. Treated cells were allografted into the mammary glands of female rats (150­190 g, 6­8 weeks) to evaluate the capability of these cells to control cancer progression and metastasis. RESULTS qPCR data revealed a significant downregulation of CDK11 and upregulation of CDH1. Cell cycle analysis and apoptosis assays indicated the knockout of CDK11 and simultaneous activation of CDH1 resulted in cell cycle arrest at G2/M phase and accumulation of cells at G2. Meanwhile, the percentage of cells that underwent late apoptosis increased in both genome editing hits. Histopathological sectioning data indicated that untransfected MCF-7 cells were capable of developing tumors in the mammary gland and initiation g angiogenesis. Transfected cells significantly restricted cancer cell infiltration/invasion by minimally localizing tumors and inhibiting angiogenesis. CONCLUSIONS Although further investigation is needed, the present data indicate the potentiality of using CRISPR/Cas9-based therapy as a promising approach to treat breast cancer. Impact: these data indicate targeting cancer-related genes via any genome editing tool might represent a novel approach to combat cancer.

Predicting Pathogenicity of CDH1 Gene Variants in Patients with Early-onset Diffuse Gastric Cancer from Western Mexico

ABSTRACT Background: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. Objective: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. Methods: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. Results: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. Conclusions: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.

Slug Inhibits Proliferation of Cervical Cancer Cells Through Down-regulating CDH3/β-catenin/C-myc Expression / 肿瘤防治研究

Objective To investigate the related mechanism of Slug inhibiting the proliferation of cervical cancer cell through CDH3/β-catenin/C-myc. Methods SiHa cells with stable Slug expression were screened. The expression of CDH3 in Slug-overexpressed SiHa cell was detected by RNA-sequence, Real-time PCR, Western blot and immunocytochemistry. The expression of CDH3 in SiHa and HeLa cells were detected by Western blot and immunocytochemistry. The protein level of CDH3 was up-regulated in HeLa cells or rescued in SiHa-Slug cells by transient transfection of CDH3 expression vector. The protein levels of β-catenin and C-myc were detected by Western blot, the cell growth was detected by cell counting and CCK-8 assays. Luciferase reporter assay and chromatin immunoprecipitation assay (ChIP) were performed to detect the effect of Slug on regulating the promoter region of CDH3. Results SiHa cell line with stable Slug expression was successfully constructed. Slug overexpression inhibited CDH3 expression in SiHa cells. CDH3 promoted cell proliferation and up-regulated the protein level of β-catenin and C-myc in HeLa and SiHa-Slug cells. Slug could recognize and bind to the E-boxes in the CDH3 promoter region and inhibited the transcription of CDH3 in SiHa cells. Conclusion Slug could inhibit the expression of β-catenin and C-myc by inhibiting CDH3 transcription in SiHa cells, and then attenuate the growth of SiHa cells.

Evaluation of long term outcome of congenital diaphragmatic hernia survivors: a single centre 8 years’ experience in a developing nation with limited facilities

Background: The objective of the study was to find out incidence of long term complications in congenital diaphragmatic hernia (CDH) survivors in a developing nation with limited facilities.Methods: A retrospective study was done on patients who underwent CDH repair at our institution from 2012 to 2019. 71 patients were identified of these 55 patients operated in neonatal age were considered. After applying exclusion criteria 42 patients included in the study were then divided in 2 groups. Group 1 (26 patients): neonates requiring ventilation within 6 hrs of birth and group 2 (16 patients): not requiring ventilation or intubated after 6hrs of birth. Data from medical records were supplemented by a questionnaire regarding perceived physical function and medical follow up till date. Respiratory, central nervous, musculoskeletal and gastrointestinal systems were concentrated upon and questionnaire set. These were then compared with respect to their long term outcomes. Also, overall incidence of these in the two groups combined was noted compared with other studies.Results: On comparing these 2 groups incidence of long term complications was found more in group 1; however on statistical analysis difference was not significant. As also incidence of individual long term complications in all patients together were identical or lower than in other published series. Mortality in our study was 8 of 49 neonates which was 17% of all patients presenting with CDH or born at our centre.Conclusions: Despite the growing population of CDH survivors the morbidity is not very significant and most patients lead a normal average active life.

Cáncer gástrico hereditario: indicaciones de estudio genético ¿cuando y a quiénes? / Hereditary gastric cancer: indications of genetic study: when and to whom?

Resumen El objetivo de esta revisión es realizar una actualización de los conocimientos actuales en cáncer gástrico hereditario, especialmente enfocado a que pacientes tienen indicación de estudio genético y su manejo clínico. En un 5-10% de los cánceres gástricos existe un patrón familiar. Los cánceres hereditarios, a diferencia de los esporádicos, se asocian a mutaciones germinales en un gen específico. En cáncer gástrico hereditario difuso (HDGC), se han identificado mutaciones en genes específicos asociados a la enfermedad (CDH1 y CTNNA1). El síndrome clínico de HDGC se asocia a la aparición a temprana edad, típicamente alrededor de los 40 años de múltiples focos de cáncer gástrico (CG) de tipo difuso, frecuentemente con células en anillo de sello y la aparición de cáncer de mama de tipo lobulillar. De los pacientes que cumplen los criterios clínicos de HDGC, el 20-50% presenta una mutación del gen CDH1. La presencia de una mutación confiere un riesgo de aparición de CG difuso de 67-70% para hombres y de 56-83% para mujeres; y un riesgo de 42% de cáncer de mama a lo largo de la vida del paciente. Se consideran actualmente como indicaciones para asesoría y estudio genético; la presencia de 2 o más familiares con CG, uno confirmado difuso, independiente de la edad; y en segundo lugar individuos con CG menores de 40 años de edad, sin historia familiar previa. Dentro del manejo de es estos pacientes es clave un equipo multidisciplinario y las principales alternativas de manejo son el seguimiento endoscópico y la gastrectomía profiláctica. Así como se ha avanzado en definir el mejor manejo clínico de estos pacientes, esta patología también representa una área de importante interés en investigación.

The aim is to update the current knowledge in hereditary gastric cancer, especially the current indications for genetic testing and its clinical management. In 5-10% of gastric cancers there is a familiar pattern. Hereditary cancers, unlike sporadic cancers, are associated with germline mutations in a specific gene. In hereditary diffuse gastric cancer (HDGC), mutations have been identified in specific genes associated with the disease (CDH1 y CTNNA1). The clinical syndrome of HDGC is associated with the appearance at an early age, typically around 40 years, of multiple foci of diffuse gastric cancer (GC), frequently with signet ring cells and the appearance of lobular type breast cancer. Twenty to fifty percent of patients who meet the clinical criteria for HDGC have a mutation in the CDH1 gene. The presence of a mutation confers a risk of diffuse CG of 67-70% for men and 56-83% for women; and a 42% risk of breast cancer throughout the life of the patient. The main current indications for genetic counseling and study are the presence of 2 or more relatives with CG, one confirmed diffuse, regardless of age; and individuals with CG less than 40 years of age, without previous family history. A multidisciplinary team is key and the main management alternatives are endoscopic follow-up and prophylactic gastrectomy. Just as there has been progress in defining the best clinical management of these patients, this pathology also represents an area of important research interest.

Association of clinicopathological features with E-cadherin (CDH1) gene-160 C>A promoter polymorphism in Turkish colorectal cancer patients

Background and Aim of Study: The role of E-cadherin (CDH1) gene-160 C>A (rs16260) promoter polymorphism in colorectal cancer (CRC) still remains inconclusive. The aim of this study is to investigate the associations between the CDH1-160 C>A polymorphism with the susceptibility and clinicopathological development of CRC in the Turkish patients. To our knowledge, this is the first report examining the role of CDH1 polymorphism in Turkish CRC patients. Materials and Methods: A total of 92 colorectal carcinoma cases (including 62 colon and 30 rectal cancer patients) and the corresponding adjacent normal tissues as controls were studied. The polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. Clinicopathological features including patient's age, gender, tumor stage, and tumor location (colon/rectum) were compared statistically with the polymorphism status. Results: There was no significant difference in both genotype and allele frequencies of the CDH1 polymorphism between colorectal tumor cases and normal samples (P = 0.472 and 0.508, respectively). Furthermore, no significant associations were observed between the CDH1 polymorphism status and age, gender, tumor stage, and tumor location of the colorectal tumor cases (all P > 0.05). Conclusions: These results indicate that CDH1-160 C>A polymorphism does not contribute to the genetic susceptibility of CRC and the polymorphism may not be a direct effect on the progression of the disease in Turkish CRC patients.

The Clinical Significance Of Rassf1a And Cdh1 Hypermethylation In Breast Cancer Patients

Introduction:Aberrant DNAmethylation patterns in serum DNAmight be used as a biomarker for the early diagnosis and management of cancer patients. The aim of present study was to evaluate DNAmethylation of RASSF1Aand CDH1 in circulating cell free DNA(cfDNA) from serum and paired tissue DNAsamples of breast cancer patients. Material and methods: Methylation-specific PCR was used to assess the methylation status of the two genes in serum and paired tissue sample DNAof 50 breast cancer patients. Biochemical parameters were assessed using an electrochemiluminescence analyzer. Results: Significant correlation found between methylation status of RASSF1A and CDH1 in serum and paired tissue samples of patients. Among clinicopathological findings, CDH1 methylation showed significant association with advance staging and tumor and methylation of RASSF1A exhibited significant association with progesterone receptor and estrogen receptor status in both serum and paired tissue. Vitamins levels were significantly high in cases compared to control group. High folic acid levels were significantly associated with the RASSF1Amethylation. Conclusions: These findings suggest that methylation of cfDNAmay be important in the early detection of breast cancer.

Methylation status of CDH1 gene in invasive ductal carcinoma of breast and its clinical significance / 重庆医学

Objective To explore the significance of gene promoter methylation of CDH1 in breast invasive ductal carcinoma.Methods The gene promoter methylation of CDH1 and E-cadherin expression status in breast cancer tissues,adjacent tissues and normal breast tissues were detected by using methylation specific polymerase chain reaction (PCR) and immunohistochemistry (SP) method.The clinicopathological data (genetic background,age,tumor size,axillary lymph node metastasis,tumor cells grading,clinical staging and molecular subtype) were collected,and analysed the clinical significance of gene promoter methylation of CDH1 in breast cancer.Results Among the 250 patients with breast cancer,113 cases were found gene promoter methylation of CDH1,and the methylation rate was 45.20％.Compared with patients with unmethylated CDH1 gene promoter,the E-cadherin protein expression was reduced in patients with methylated CDH1 gene promoter,there was statistically significant difference (x2 =21.360,P＜0.01).The univariate analysis showed that statistically significant differences were found in axillary lymph node metastasis (x2=19.086,P＜0.01),histological grading of tumor (x2 =8.487,P=0.014),CerbB-2 expression (x2=9.475,P=0.002) and molecular typing (x2 =25.482,P＜0.01) between patients with methylated and unmethylated CDH1 gene promoter.The COX regression analysis showed that there was significant difference in 5-year survival rate between patients with methylated and unmethylated CDH1 gene promoter(P＜0.01).Conclusion Methylation of CDH1 gene promoter causes decreasedexpression of mRNA,and is associated with axillary lymph node metastasis in breast cancer,which suggests that methylation of CDH1 gene promoter plays a certain role in breast cancer progression.

Study on role of CDH17 regulating TGF-β autocrine for affecting invasion of gastric cancer cells / 重庆医学

Objective To explore the role and possible mechanism of transforming growth factor (TGF)-β autocrine in CDH17 regulating invasion of gastric cancer cells.Methods Construction and transfection of siRNA-CDH17 into MKN-45 gastric cancer cell line to silence the expression of CDH17.Expression of TGF-β and concentrations of TGF-β in supernatants were detected before and after CDH17 silence by immunofluorescence,immunoblotting and ELISA.The autocrine situation of TGF-β was observed.Meanwhile,the activation of TGF-β/Smad3 signaling pathway was also detected by immunoblot.After giving signaling pathway inhibitor,the changes of invasion ability of MKN-45 cells were observed by Transwell invasion experiment.The role of TGF-β autocrine and related signaling pathway activation in CDH17-regulated invasion of gastric cancer cells was evaluated.Results After transfecting siRNA-CDH17 for silencing CDH17 expression in MKN-45 cells,the expression of TGF-β was significantly decreased compared with non-transfection group,its concentration in supernatants was also significantly reduced[(510 ±55)pg/mL vs.(115±20) pg/mL,P<0.01].The immunoblots revealed that phosphorylation level of Smad3 after CDH17 silence was also significantly diminished.However,giving the TGF-β/Smad3 signaling inhibitor SIS3 (10 μmol/L) could also suppress the phosphorylation level of Smad3 when CDH17 was highly expressed,meanwhile silencing CDH17 and inhibiting Smad3 phosphorylation could significantly decrease the invasion of MKN-45 gastric cancer cells (P<0.05).Conclusion CDH17 could participate in the invasion of gastric cancer cells by promoting TGF-β autocrine to activate TGF-β/Smad3 signaling pathway.

CDH13 Genetic Polymorphisms, Adiponectin and Ischemic Stroke: a Chinese Family-based Sib-pair Study / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors.</p><p><b>METHODS</b>We recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model.</p><p><b>RESULTS</b>In individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = -0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = -0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = -0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001).</p><p><b>CONCLUSION</b>CDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.</p>

Progress in Diagnosis and Treatment of Hereditary Diffuse Gastric Cancer / 胃肠病学

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited disease,and may be related to the mutation of CDH1 or CTNNA1 genes.Microscopically,signet-ring cell carcinoma is suggested frequently in endoscopic biopsy or gastrectomy specimens.Some patients may have concomitant extra-stomach tumor (frequently breast cancer in females).Detection of CDH1 gene mutation should be performed in high-risk individuals,and diagnosis and treatment should be carried out by a multidisciplinary team.Prophylactic gastrectomy is recommended for those with pathogenic CDH1 mutation.Endoscopic surveillance is an option for those with CDH1 mutation of undetermined significance and those without germline CDH1 mutation.This review discussed the concept,genetic characteristics,clinicopathological features and genetic screening of HDGC for providing a reference for clinicians.

Predictive effect of serum CDH13 methylation for progression after TURBT in patients with non-muscle invasive bladder cancer / 重庆医学

Objective To investigate the predictive effect of serum CDH13 methylation for the progression after TURBT in the patients with non-muscle invasive bladder cancer.Methods Ninety-eight patients with non-muscle invasive bladder cancer treated by TURBT in this hospital from January 2010 to January 2012 were selected.The methylation specific PCR was used to detect the methylation status of serum CDH13.Then its correlation with the clinicopathological data as well as postoperative progression situation was analyzed.Results Serum CDH13 methylation was detected in 52 cases (53.1％),moreover serum CDH13 methylation was closely correlated with tumor size,grade and number (P＜0.05).During follow-up,20 cases (20.4％) appeared the tumor progression.The Kaplan-Meier analysis and log-rank test found that the patients with serum CDH13 methylation had shorter progression-free survival rate than the patients without serum CDH13 methylation,and the difference was statistically significant (P=0.007).The Cox regression analysis showed that serum CDH13 methylation was an independent risk factor for the progression after TURBT in non-muscle invasive bladder cancer.Conclusion Serum CDH13 methylation can serve as a predictive indicator of the progression after TURBT in non-muscle invasive bladder cancer.

Mutation analysis of causative genes in a case of congenital hypotrichosis / 中华皮肤科杂志

Objective To identify the genetic cause of a case of congenital hypotrichosis by a nextgeneration sequencing technology.Methods A 9-year and 3-month-old girl presented with few villous hairs at birth,which grew slowly.Skin examination showed sparse,thin,soft,woolly and light-yellow hairs,small amount of hairs on the top of the head and a less amount of hairs around the head,hairline recession and broadened forehead.No abnormality was found by ophthalmic examination.No similar aberrant phenotype was observed in the patient's parents or her younger sister.Her parents were non-consanguineous marriage.Peripheral venous blood samples were obtained from the patient,her mother and younger sister.Genomic DNA was extracted and then analyzed by a next-generation sequencing technology.The suspected pathogenic mutations were validated by Sanger sequencing and subjected to bioinformatics analysis.Results Two mutations were identified in the CDH3 gene in the patient,including a c.1057G ＞ T (p.D353Y) heterozygous mutation in exon 5 and a c.1767delC (p.I589Ifs) heterozygous mutation in exon 10.They were both novel mutations,and their pathogenicity was predicted by softwares.Sanger sequencing indicated that the c.1057G ＞ T (p.D353Y) heterozygous mutation was inherited from the patient's mother,and gene transfer analysis revealed that the c.1767delC (p.I589Ifs) heterozygous mutation was inherited from the patient's father.Conclusion The c.1057G ＞ T (p.D353Y) and c.1767delC (p.I589Ifs)heterozygous mutations may cause hypotrichosis and juvenile macular dystrophy in the patient,so careful observation and comprehensive ophthalmic examination should be performed on time for early diagnosis and treatment of eye symptoms.

Helicobacter pylori Eradication Modulates Aberrant CpG Island Hypermethylation in Gastric Carcinogenesis / 대한소화기학회지

BACKGROUND/AIMS: Helicobacter pylori infection induces aberrant DNA methylation in gastric mucosa. We evaluated the long-term effect of H. pylori eradication on promotor CpG island hypermethylation in gastric carcinogenesis. METHODS: H. pylori-positive patients with gastric adenoma or early gastric cancer who underwent endoscopic resection were enrolled. According to H. pylori eradication after endoscopic resection, the participants were randomly assigned to H. pylori eradication or non-eradication group. H. pylori-negative gastric mucosa from normal participants provided the normal control. CpG island hypermethylation of tumor-related genes (p16, CDH1, and RUNX-3) was evaluated by quantitative MethyLight assay in non-tumorous gastric mucosa. The gene methylation rate and median values of hypermethylation were compared after one year by H. pylori status. RESULTS: In H. pylori-positive patients, hypermethylation of p16 was found in 80.6%, of CDH1 in 80.6%, and of RUNX-3 in 48.4%. This is significantly higher than normal control (p16, 10%; CDH1, 44%; RUNX-3, 16%) (p<0.05). In the H. pylori eradication group, methylation rates of p16 and CDH1 decreased in 58.1% and 61.3% of the patients, and the median values of hypermethylation were significantly lower at one year compared with the non-eradication group. However, RUNX-3 hypermethylation did not differ significantly at one year after H. pylori eradication. The non-eradication group hypermethylation did not change after one year. CONCLUSIONS: H. pylori infection was associated with promotor hypermethylation of genes in gastric carcinogenesis, and H. pylori eradication might reverse p16 and CDH1 hypermethylation.

The Correlation of CDH13 Gren Variation with Non-small Cell Lung Cancer / 昆明医科大学学报

Objective To evaluate the correlation of the single nucleotide polymorphisms (SNPs) in CDH13 with non-small cell lung cancer (NSCLC) . Methods 115 patients with NSCLC and 110 healthy controls were included in present study. Two SNPs (rs11646213 and rs7195409) in CDH13 were genotyped using TaqMan method. The association of these two SNPs with NSCLC was calculated and assessed. Results The genotypic and allelic frequencies of rs11646213 showed significant difference between NSCLC patients and the control group (P<0.05), (OR=0.464, 95% CI:0.273~0.789) . The genotypic and allelic frequencies of rs7195409 showed significant difference between the stage I+II and stage III+IV groups (P<0.05), (OR=0.491, 95% CI:0.243~0.991) . Conclusions The rs16146213 has a strong association with NSCLC and G allelic showed a protective effect. The rs7195409 has a strong association between stage I+II and III+IV in NSCLC, and G allele may play a protective role in the development of NSCLC.

The Impact of CDH13 Polymorphism and Statin Administration on TG/HDL Ratio in Cardiovascular Patients

PURPOSE: Adiponectin is expressed in adipose tissue, and is affected by smoking, obesity, and genetic factors, such as CDH13 polymorphism, contributing to the development of coronary vascular diseases (CVDs). MATERIALS AND METHODS: We investigated the effect of genetic variations of CDH13 (rs3865188) on blood chemistry and adiponectin levels in 345 CVD patients undergoing statin-free or statin treatment. RESULTS: Genetic variation in CDH13 was significantly correlated with several clinical factors, including adiponectin, diastolic blood pressure, triglyceride (TG), and insulin levels. Subjects with the T allele (mutant form) had significantly lower adiponectin levels than those with the A allele. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), TG/high-density lipoprotein cho-lesterol (HDLc) ratio, and HDL3b subtype were markedly decreased in statin treated subjects regardless of having the A or T allele. TG and TG/HDL in the statin-free group with TT genotype of the rs3865188 was higher than in the others but they were not different in the statin-treated subjects. We observed a significant difference in adiponectin levels between patients with the A and T alleles in the statin-free group; meanwhile, no difference in adiponectin levels was noted in the statin group. Plasma levels of other cytokines, leptin, visfatin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), were not different among the CDH13 genotypes according to statin administration. Body mass index (BMI), TG, insulin, HDL3b, and TG/HDL ratio showed negative correlations with adiponectin levels. CONCLUSION: Plasma adiponectin levels and TG/HDL ratio were significantly different according to variants of CDH13 and statin administration in Korean patients with CVD.

Presymptomatic Identification of CDH1 Germline Mutation in a Healthy Korean Individual with Family History of Gastric Cancer

Gastric cancer (GC) is one of the most common cancers with high morbidity and mortality. Familial GC is seen in 10% of cases, and approximately 3% of familial GC cases arise owing to hereditary diffuse gastric cancer (HDGC). CDH1, which encodes the protein E-cadherin, is the only gene whose mutations are associated with HDGC. Screening for the familial GC-predisposing gene has been neglected in high-risk countries such as Korea, China, and Japan, where all the cases have been attributed to Helicobacter pylori or other carcinogens. Screening for the GC-causing CDH1 mutation may provide valuable information for genetic counseling, testing, and risk-reduction management for the as-yet unaffected family members. An asymptomatic 44-yr-old Korean male visited our genetic clinic for consultation owing to his family history of GC. Eventually, c.1018A>G in CDH1, a known disease-causing mutation, was found. As of the publication time, the individual is alive without the evidence of GC, and is on surveillance. To our knowledge, this is the first Korean case of presymptomatic detection of CDH1 mutation, and it highlights the importance of genetic screening for individuals with a family history of GC, especially in high-risk geographical areas.

Association between CDH13 Variants and Cardiometabolic and Vascular Phenotypes in a Korean Population

PURPOSE: Although some CDH13 single nucleotide polymorphisms (SNPs) have been shown to be determinants of blood adiponectin levels, the clinical implications of CDH13 variants are not yet completely understood. The purpose of this study was to evaluate the effects of SNPs of CDH13 on metabolic and vascular phenotypes. MATERIALS AND METHODS: We included 238 hypertensive subjects and 260 age- and sex-matched controls. Seven tagging-SNPs were identified in the CDH13 gene by whole gene sequencing. The association between these SNP variants and the risk of hypertension, metabolic traits, and carotid intima-media thickness (IMT) was examined. RESULTS: Minor allele carriers of rs12444338 had a lower risk of hypertension, but the association turned out just marginal after adjusting confoudners. Blood glucose levels were higher in the minor allele carriers of c.1407C>T (p=0.01), whereas low-density lipoprotein-cholesterol levels were greater in those of rs6565105 (p=0.02). The minor allele of rs1048612 was associated with a higher body mass index (p=0.01). In addition, the mean carotid IMT was significantly associated with rs12444338 (p=0.02) and rs1048612 (p=0.02). CONCLUSION: These results provide evidence that CDH13 variants are associated with metabolic traits and carotid atherosclerosis in Koreans. This study shows the multifaceted effects of CDH13 variants on cardiometabolic risk.