A novel truncating mutation in the E-cadherin gene in the first Iranian family with hereditary diffuse gastric cancer

Aims

Hereditary Diffuse Gastric Cancer (HDGC) is a dominantly inherited familial cancer syndrome resulting from germline mutations of the E-cadherin (CDH1) gene. The first Iranian family with HDGC is herein reported.

Methods

The family fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria for HDGC. The entire coding region of the CDH1 gene was analysed by direct sequencing in an obligatory carrier. Subsequent molecular genetic tests were done on other at risk individuals to identify mutation carriers.

Results

A novel heterozygous 2275G>T mutation in exon 14 of the CDH1 gene was detected. This nonsense mutation generates a premature stop codon at position 758 giving rise to a truncated E-cadherin protein lacking cytoplasmic region. The specified mutation was detected in the index case and her asymptomatic son who underwent prophylactic gastrectomy.

Conclusion

The first Iranian family with HDGC which carries a novel CDH1 germline mutation is reported.     

Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family.

AIMS: Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations. METHODS: The entire coding region of the CDH1 gene and all intron-exon boundaries were analyzed by direct sequencing in the 14 families fulfilling the IGCLC criteria. E-cadherin immunohistochemical expression was evaluated on tumour as well as normal formalin-fixed paraffin embedded tissues. RESULTS: A novel germline missense mutation was found. It was a single C-->T substitution in exon 8, resulting in a transition of CCG-->CTG (C1118T; Pro373Leu) demonstrated in the proband and her brother. At immunohistochemical analysis, the staining intensity was reduced and considered weakly positive (15%). CONCLUSIONS: The first CDH1 germline mutation of an Italian family is herein reported. The present missense mutation has never been described so far.     

Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer

Background. E-cadherin has been recognized as an impor-tant factor associated with tumor metastasis. However, the relationship between micrometastasis in the lymph nodes and the expression of E-cadherin in the primary tumor in gastric cancer remains unclear. Methods. Two consecutive sections of 4522 lymph nodes from 162 patients with early gastric cancer were prepared for simultaneous hematoxylin and eosin (H&E) and cytokeratin (CK) staining. Sections of primary tumors from 135 of these patients were prepared for E-cadherin immunostaining. Results. The incidence of lymph node involvement was significantly increased, from 6.8% (11/162 patients) by H&E staining, to 27% (43/162 patients) by CK immunostaining ( P < 0.0001). Micrometastasis in the lymph node was found in 32 of 151 (21%) patients who had no lymph node metastasis evidenced by H&E staining. Micro-lymph node metastasis was frequently found in tumors with a diameter more than 1.0 cm, of those that were poorly differentiated, deeply invaded, showed lymphatic on vascular invasion, and in those that showed reduced expression of E-cadherin. Loss of expression of E-cadherin in the primary tumor was closely correlated with micro-lymph node metastasis. Patients with tumors with micro-lymph node metastasis detected by CK immunostaining had a significantly lower 5-year survival rate ( P < 0.01) than those without such metastases. Conclusion. Tumors more than 1.0 cm in diameter and those that exhibit poor differentiation, deep invasion (i.e., to the submucosa), lymphatic or vascular invasion, and reduced expression of E-cadherin are risk factors for lymph node metastasis in early gastric cancer. Thus, it is recommended that cancers confined to the mucosa (m-cancers) that are more than 1.0 cm in diameter should not be treated with limited surgery without lymphadenectomy. Received: March 27, 2001 / Accepted: May 10, 2001     

Detection of early gastric cancer: misunderstanding the role of mass screening

Background The proportion of early gastric cancer (EGC) increased from 15% during the 1960s to 50% recently, leading to a remarkable improvement of the 5-year survival rate of gastric cancer patients from 40% to 70%. This has been attributed to mass screening together with extended lymphadenectomy. However, more and more patients with EGC are diagnosed outside of mass screening. The aim of this study was to determine whether patients are symptomatic at the time of early detection and the method of tumor detection. Methods From 2001 to 2003, a total of 1226 patients (male/female 2.2 : 1.0, age 26–95 years) with EGC were treated at the National Cancer Center Hospital, Tokyo. We reviewed their medical records. Results Of these 1226 patients, 512 (41.8%) were symptomatic, and 714 (58.2%) reported no symptoms. Among the symptomatic patients, 468 (91.4%) were examined at outpatient clinics, 39 (7.6%) by private health assessment clinics, and 5 (1.0%) by mass screening. In total, 91.6% of the symptomatic patients directly underwent esophagogastro-duodenoscopy (EGD). Of the asymptomatic patients, 320 (44.8%) were examined at outpatient clinics, 306 (42.9%) by private health assessment clinics, and 88 (12.3%) by mass screening. EGD was the initial assessment in 67.8% and radiography in 32.2% of asymptomatic patients. Conclusion Most patients with EGC were detected outside of mass screening. This suggests that the Japanese public and physicians are well aware of the risk of gastric cancer and the importance of early detection. The effect of mass screening is misunderstood.     

Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs.

BACKGROUND: Hypermethylation is studied as a new, relevant mechanism for silencing tumor suppressor genes. It is a potentially reversible epigenetic change and it is the target of novel anticancer compounds with demethylating activity. In this perspective, we investigated E-cadherin gene (CDH1) promoter hypermethylation in gastric carcinomas and its correlation with E-cadherin protein expression. METHODS: Consecutive cases of gastric carcinoma with assessable paraffin-embedded tumor blocks and paired normal mucosa were considered eligible for study entry. CDH1 promoter hypermethylation and E-cadherin protein expression were determined by methylation-specific polymerase chain reaction and immunohistochemistry, respectively. RESULTS: CDH1 promoter hypermethylation was found in 20 out of 70 gastric carcinomas and the epigenetic change occurred in the early, as well as in the locally advanced disease. In five cases, hypermethylation was also detected in the normal mucosa. Eighteen out of 20 hypermethylated tumors were of the diffuse histotype (P=0.0001). Of 24 tumors with reduced or negative E-cadherin expression, 19 were hypermethylated and 5 were unmethylated (P=0.0001). CONCLUSIONS: CDH1 promoter hypermethylation frequently occurs in gastric carcinomas of the diffuse histotype and it is significantly associated with downregulated E-cadherin expression. The knowledge on the hypermethylation status of tumor suppressor genes may be relevant to the development of demethylating drugs and novel chemopreventive strategies in solid tumors.     

沉默信息调节因子-1及上皮性钙黏附素在胃癌中的表达及其相关性

目的:探讨沉默信息调节因子-1(silence signal regulating factor-1,SIRT-1)和上皮性钙黏附素(epithelial cadherin,E-cadherin)在胃癌组织中的表达及其相关性。方法:采用HE 染色观察正常胃黏膜组织及癌组织的病理结构;采用免疫组织化学方法检测SIRT-1和E-cadherin在正常胃黏膜组织及癌组织中的表达水平;Spearman相关检验检测SIRT-1 与E-cadherin 表达的相关性。结果:HE 染色结果:胃癌组织中癌细胞分化差,多形性,大小不一,可呈假复层,核大,胞浆少,容易找到核分裂。免疫组织化学检测结果:SIRT-1在正常胃黏膜组织和胃癌组织的阳性表达率分别为40.5%和64.3%;E-cadherin 的阳性表达率分别为73.8%和40.5%。两组SIRT-1和E-cadherin的阳性表达率差异有统计学意义（P<0.05）。Spearman相关分析显示SIRT-1 与E-cadherin 的表达水平呈负相关（P<0.05）。胃癌组织中SIRT-1蛋白阳性表达与肿瘤大小及病理类型有关（P<0.05）;而与患者的年龄、性别、TNM分期及淋巴结转移无关（P>0.05）。结论:胃癌组织中SIRT-1高表达可能通过抑制E-cadherin促使肿瘤组织细胞发生侵袭、转移。     

早期胃癌组织中生存素表达的临床意义

目的检测生存素在早期胃癌中的表达及其临床意义。方法利用逆转录聚合酶链反应检测30例早期胃癌及正常人胃黏膜组织中生存素的表达率,分析生存素与早期胃癌的关系。结果早期胃癌组织中生存素表达率96．7％,正常人则胃黏膜中生存素的表达率为0％。结论生存素在早期胃癌组织中有较高的表达率,其表达与胃癌的预后呈正相关,可作为早期胃癌的检测指标。     

Cost-benefit analysis of screening for esophageal and gastric cardiac cancer

In 2005, a program named Early Detection and Early Treatment of Esophageal and Cardiac Cancer (EDETEC) was initiated in China. A total of 8279 residents aged 40-69 years old were recruited into the EDETEC program in Linzhou of Henan Province between 2005 and 2008. Howerer, the cost-benefit of the EDETEC program is not very clear yet. We conducted herein a cost-benefit analysis of screening for esophageal and cardiac cancer. The assessed costs of the EDETEC program included screening costs for each subject, ...     

胃癌家族史与胃癌患者临床病理特征及预后的关系

目的探讨有、无胃癌家族史的胃癌患者之间临床病理特征及预后的差异。方法回顾性分析2011年至2015年456例胃癌患者的临床病例资料,其中有胃癌家族史者102例。采用双侧χ~2检验分析有、无胃癌家族史患者的临床病理特征;生存分析用Kaplan-Meier法,并行Log-rank检验;用Cox比例风险模型分析影响胃癌预后的因素。结果在有胃癌家族史的患者中,年龄≥50岁、肿瘤最大径<5 cm、组织学分级为Ⅰ~Ⅱ级以及M_0分期的比例均显著高于无胃癌家族史者(P<0.05)。有胃癌家族史患者的中位总生存时间(OS)为56.1个月,高于无胃癌家族史者的51.0个月(P=0.318);但在发病年龄<50岁的亚组中,有胃癌家族史患者的中位OS显著优于无胃癌家族史患者(未达vs.53.0个月,P=0.021)。Cox比例风险模型显示,影响有胃癌家族史患者OS的因素为N分期和M分期(P<0.05),影响无胃癌家族史患者OS的因素为肿瘤最大径、肿瘤部位和M分期(P<0.05)。结论有、无胃癌家族史的胃癌患者之间存在临床病理特征的差异,其OS亦可能存在差异。     

Effect of annual endoscopic screening on clinicopathologic characteristics and treatment modality of gastric cancer in a high-incidence region of Korea

We investigated risk factors for gastric cancer (GC) and effect of annual endoscopic screening on detection and treatment modality of GC. Asymptomatic adults who underwent upper endoscopy during health checkups at Seoul National University Hospital Healthcare System Gangnam Center were enrolled. We compared clinicopathologic characteristics of GC according to screening interval (repeated vs. infrequent, annual vs. biennial). After age- and sex-matching, relative risk was computed by hazard ratio (HR) using Cox proportional regression with multivariate adjustment. Of the 58,849 subjects who received screening endoscopy, 277 (0.47%) were found to have GC. Intestinal type comprised 55.4% (102/184) followed by diffuse type (n = 65, 35.3%). Age ≥50 years, family history and smoking independently increased the risk of GC for both types, whereas male gender [HR = 4.81, 95% confidence interval (CI): 2.72-8.03] and intestinal metaplasia (IM) (HR = 10.87, 95% CI: 3.36-22.30) were significant predictors for intestinal type only. Proportion of early gastric cancer (EGC) was 98.6% (71/72) in annual screening group and 80.7% (46/57) in biennial screening group (p < 0.01). In the former, tumor size was smaller (1.7 ± 1.3 vs. 2.3 ± 1.8 cm; p < 0.01] and proportion of intramucosal cancer was larger (75.0 vs. 56.1%; p = 0.04). Endoscopic resection was performed more frequently in annual screening group (56.9 vs. 33.3%; p = 0.02). IM along with male gender and older age was a strong risk factor for intestinal type GC. Annual screening group improved detection of early-stage and endoscopically treatable GC suggesting that intensive screening and surveillance may be useful for high-risk subpopulations with epidemiologic risk factors or premalignant lesions such as IM.     

Gastric cancer screening and subsequent risk of gastric cancer: a large-scale population-based cohort study, with a 13-year follow-up in Japan

We prospectively investigated the association between gastric cancer screening and subsequent risk of gastric cancer in a large-scale population-based prospective cohort study, with a 13-year follow-up in Japan. Data were analyzed from a population-based cohort of 42,150 (20,326 men and 21,824 women) subjects. Approximately 36% of subjects reported that they had undergone screening photofluorography during the preceding 12 months, and were regarded as the screened group. A total of 179 gastric cancer deaths and 636 incident gastric cancers were identified during the follow-up period. We observed a 2-fold decrease in gastric cancer mortality in screened versus unscreened subjects (RR = 0.52; 95% CI = 0.36-0.74). The extent of the reduction in mortality for gastric cancer was greater than in death from all causes excluding gastric cancer (RR = 0.71; 95% CI = 0.65-0.78). A significant decrease in the incidence of advanced gastric cancer was observed in screened subjects (RR = 0.75; 95% CI = 0.58-0.96), although the overall incidence rate did not differ significantly between the screened and unscreened subjects (RR = 1.06; 95% CI = 0.90-1.25). In age-stratified analyses, a significant reduction in gastric cancer mortality was seen in screened subjects aged 40-49 years at baseline, compared with a lesser reduction in screened subjects aged 50-59 (RR = 0.30, 95% CI = 0.13-0.72; and RR = 0.60, 95% CI = 0.40-0.88, respectively). These findings suggest that gastric cancer screening may be associated with a reduced risk of mortality from gastric cancer.     

门诊症状患者早期胃癌及癌前病变的发病情况及特点

目的:了解门诊患者早期胃癌及癌前病变的发病情况及其特点,探讨对于症状性患者胃镜检查的重要性。方法:选择门诊因有消化道症状行电子胃镜检查的患者,进行标准的胃镜检查和染色,记录其基础资料及临床资料,分析早期胃癌及癌前病变的发病情况及其特点。结果:慢性萎缩性胃炎、肠上皮化生、胃癌及异型增生的检出率分别为:53.96%、7.64%、4.96%。男性和高龄均为三者的危险因素。结论:门诊症状性患者早期胃癌及癌前病变的检出率相对较高,应加强胃镜筛查。     

Lymph node metastasis and preoperative diagnosis of depth of invasion in early gastric cancer

Background. No reports have, to date, focused on the relationship between preoperative determination of the depth of invasion and lymph node metastasis. The present study, under the leadership of the Japanese Gastric Cancer Association, was designed to form a basis for decision making in limited treatment for early gastric cancer (EGC). Methods. From eight major hospitals in Japan, 2672 gastric cancers whose preoperative depth of invasion was mucosal(M-cancer), and 6209 EGCs, consisting of 3584 mucosal(m-) and 2625 submucosal(sm-) cancers, were collected by questionnaire. All registered patients underwent gastrectomy with D1 or more extensive lymphadenectomy between 1985 and 1998. Results. The accuracy of preoperative diagnosis of depth of invasion of M-cancers was 80.2% (2144/2672). However, of the total of 2432 M-cancers in which no nodal involvement was observed intraoperatively (N0), histological examination of the resected specimens confirmed that lymph node metastasis was absent in 2353 (96.8%). The frequencies of lymph node metastasis in early gastric, m-, and sm-cancers were 8.9%, 2.5%, and 17.6%, respectively. Node involvement was associated with a higher frequency of undifferentiated than differentiated histology, as well as with greater tumor size. The incidences of lymph node metastasis in m-cancers with a diameter of less than 4 cm, and in sm-cancers with a diameter below 1 cm were 1.3% (37/2837) and 4.9% (4/82), respectively. These metastases rarely extended beyond the first tier. Conclusion. N0 and M-cancers, m-cancers less than 4 cm in diameter, and sm-cancers no larger than 1 cm in diameter may be appropriate indications for limited surgery. Received: January 23, 2001 / Accepted: March 15, 2001     

MUC-5AC核粘蛋白在早期胃癌中的表达和意义

目的探讨胃正常粘膜、不典型增生以及早期胃癌中MUC-5AC核粘蛋白的表达状态及临床病理意义.方法应用免疫组织化学s-p法检测人正常胃粘膜、不典型增生及早期胃癌组织中的表达.结果人正常胃粘膜中浅表1/3范围内广泛分布MUC-5AC核粘蛋白(100%).不典型增生和早期胃癌组织中表达的阳性率分别为70%和41.7%.早期胃癌中MUC-5AC核粘蛋白的表达与患者的性别、肿物的部位、大小、浸润深度、淋巴结转移和分化程度、异型度及癌旁肠化生和癌旁淋巴反应无关(P＞0.05).但与Laurem's分型(肠型、胃型、混合型)密切相关,且差异显著(P＜0.05).结论 MUC-5AC核粘蛋白在胃粘膜不典型增生和胃癌早期阶段即出现不同程度的异常表达,整个过程呈下调趋势.且与Lauren's分型密切相关.     

Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer

beta-catenin, a component of the E-cadherin-catenin cell adhesion complex, also plays a separate intracellular signalling role, interacting with APC protein. Intracellular accumulation of beta-catenin is common in colorectal neoplasia. beta-catenin abnormalities are associated with poor survival in gastric cancer, but previous studies do not differentiate between membrane-associated and intracellular beta-catenin. In this study we aimed to determine which type of expression abnormalities for E-cadherin, beta-catenin and alpha-catenin correlate with clinico-pathological features and survival in gastric cancer. Immunoperoxidase staining of paraffin-embedded sections from 40 gastric cancers was performed for E-cadherin, alpha- and beta-catenins using microwave unmasking and an avidin-biotin technique. Clinical data were obtained from case records and cancer registry records. Reduced membranous expression of beta-catenin occurred in 10/12 (83%) diffuse and 8/28 (29%) intestinal tumours (P= 0.0014), and was associated with poor differentiation (P= 0.0015) and short survival (P= 0.032), but not with age, sex, tumour size or nodal status. Nuclear expression of beta-catenin was uncommon; cytoplasmic expression was observed in 13/40 cases (33%) but did not correlate with histology, tumour grade or survival. Reduced E-cadherin membrane expression was associated with lymph node metastasis (P= 0.02). Neither E-cadherin or alpha-catenin expression correlated with survival. Reduced membranous expression of beta-catenin predicts poor prognosis in gastric cancer, whilst ectopic intracellular expression is relatively rare. The apparent differences in beta-catenin expression from those found in colon cancer merit further study.     

基于转录组测序分析弥漫型胃癌特征及其核心基因LUM的表达

目的 分析弥漫型胃癌的转录组特征并对核心基因LUM(Lumican)的表达进行验证.方法 收集2021年1月—2021年12月广西医科大学附属肿瘤医院手术切除的29例胃癌患者癌组织及其配对癌旁正常组织标本,取其中5例弥漫型胃癌组织进行转录组测序并获取基因表达谱,再利用差异基因进行GO和KEGG富集分析,使用cytosc...     

Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil

Background

Hereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil.

Methods

Twenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern.

Results

No evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents.

Conclusion

This is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study.     

Expression of TGF-β1, Snail, E-cadherin and N-cadherin in Gastric Cancer and Its Significance

OBJECTIVE To investigate the expression of TGF-β1,Snail,E-cad-herin and N-cadherin in gastric cancer(GC),and to examine its relationship to malignant features of the tumors. METHODS The expression of TGF-β1,Snail,E-cadherin and N-cadherin proteins was detected in GC and adjacent tissues by immunohistochemical staining,and compared with the clinico-pathological data. RESULTS Positive rates of expression for TGF-β1,Snail,E-cadherin and N-cadherin were 63.5%,83.3%,37.5%and 44.8%in GC,and 28.8%, 41.3%,100%,11.3%in adjacent tissues,respectively.The expression of all four proteins showed a significant difference between the GCs and adjacent tissues(P<0.05).The positive rate of TGF-β1,Snail and N-cadherin,or the negative rate of E-cadherin expression was significantly related to the differentiated degree,histological type,invasion and metastasis of GC.In addition,the expression of N-cadherin was positively related to that of TGF-β1, but negatively related to that of E-cadherin.There was negative correlation between expression of E-cadherin and TGF-β1 and Snail in GC(P<0.05). CONCLUSION The over-expression of TGF-β1 and Snail and decreased expression of E-cadherin and the abnormal expression of N-cad-herin were involved in the process of invasion and metastasis of GC.The data showed that E-cadherin might switch to N-cadherin.TGF-β1 and Snail might play a fundamental role in the process.     

Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.