Familial Gastric Cancer Patients Research Articles

Analysis of clinicopathological characteristics and prognosis of 91 patients with familial gastric cancer

To explore the clinicopathological characteristics and prognosis of familial gastric cancer(FGC) and to provide clinical evidence for rational treatment program. Clinicopathological data of 91 patients with FGC and 293 patients with sporadic gastric cancer(SGC) in our department from March 2003 to October 2007 were retrospectively analyzed and compared between the two groups. Tumors with a diameter of less than or equal to 5 cm were more common in FGC patients than SGC patients [65.9%(60/91) vs. 52.6%(154/293), P=0.025]. Proportion of FGC patients with poor differentiation was significantly higher as compared to SGC patients [68.1%(62/91) vs. 55.6%(163/293), P=0.034]. The 5-year overall survival rate in FGC patients was significantly lower than that in SGC patients(25.6% vs. 38.9%, P=0.001). Further stratified analysis revealed that the 5-year survival rates of T4 FGC and T4 SGC patients were 14.5% and 30.5% respectively, the 5-year survival rates of N3 FGC and N3 SGC patients were 10.4% and 17.3% respectively, and the differences were statistically significant(all P<0.05), while other T stage and N stage between the two groups were not significantly different(all P>0.05). Univarite analysis showed that tumor size, tumor location, pathological type, operation method, infiltration depth and lymph node metastasis were influencing factors of prognosis of FGC. Multivariate analysis showed that tumor size(HR=2.271), pathology types(HR=1.449), lymph node metastasis(HR=1.748) and the infiltration depth(HR=1.487) were independent risk factors affecting the prognosis of patients with FGC. Compared with SGC, FGC is associated with poor differentiation and poor prognosis.

A Registry Program for Familial Gastric Cancer Patients Referred to Cancer Institute of Iran

Gastric cancer is the second most common cause of cancer death. It has a poor prognosis with only 5-10% of hereditary etiology. If it is diagnosed, it could be helpful for screening the other susceptible members of a family for preventive procedures. Usually it is identified by symptoms such as presence of cancer in different members of family, some special type of pathology such as diffused adenocarcinoma, having younger age and multiple cancer syndromes. Hence, designing a registry program can be a more practical way to screen high risk families for a preventive program. Based on the inclusion criteria, a questionnaire was prepared. After pilot on a small number of patients, the actual data was collected from 197 patients and processed in SPSS 16.0. Totally, 11.8% of the patients were younger than 45 years old. Blood type 'A' was dominant and males had a higher risk behavior with higher consumption of unhealthy food. Adenocarcinoma was reported in majority of cases. 21.8% of the patients had the including criteria for familial gastric cancer (FGC). The high percentage of FGC population compared to the other studies have revealed a need to design an infrastructural diagnostic protocol and screening program for patients with FGC, plus preventive program for family members at risk which could be done by a precise survey related to frequency and founder mutations of FGC in a national registry program.

The risk of gastric cancer in carriers of CHEK2 mutations

CHEK2 is a tumor suppressor gene whose functions are central to the induction of cell cycle arrest and apoptosis following DNA damage. Mutations in CHEK2 have been associated with cancers at many sites, including breast and prostate cancers, but the relationship between CHEK2 and gastric cancer has not been extensively studied. In Poland, there are four known founder alleles of CHEK2; three alleles are protein truncating (1100delC, IVS2G>A, del5395) and the other is a missense variant (I157T). We examined the frequencies of four Polish founder mutations in the CHEK2 gene in 658 unselected gastric cancer patients, in 154 familial gastric cancer patients and in 8,302 controls. A CHEK2 mutation was seen in 57 of 658 (8.7 %) unselected patients with gastric cancer compared to 480 of 8,302 (5.8 %) controls (OR 1.6, p = 0.004). A CHEK2 mutation was present in 19 of 154 (12.3 %) familial cases (OR = 2.3, p = 0.001). The odds ratio for early onset (<50 years) gastric cancer was higher (2.1, p = 0.01), than for cases diagnosed at age of 50 or above (OR 1.4, p = 0.05). Truncating mutations of CHEK2 were associated with higher risk (OR = 2.1, p = 0.02) than the missense mutation I157T (OR = 1.4, p = 0.04). CHEK2 mutations predispose to gastric cancer, in particular to young-onset cases.

Mutations and polymorphisms of genes moderate increase in gastric cancer risk

Results of studies performed in our center point at DNA changes of many cancer (mostly moderate) susceptibility genes. Association of weak mutations and polymorphism of many genes and additional influence of environmental factors can significantly increase the risk of cancer development. The preliminary studies performed in our department indicate, that increased risk of gastric cancer may be related to mutation in NOD2 and CHK2 genes predisposing to cancers of many organs. The CHEK2 gene encodes checkpoint kinase 2 (Chk2), it acts as a tumor suppressor whose functions are central to the induction of cell cycle arrest and apoptosis by DNA damage. Results of studies performed in our center indicate that the frequency of the IVS2+1G→A alteration was significantly increased in a group of 658 consecutive patients, especially in those under 50 years of age (OR=5.332, p=0.0174). I157T was over-represented in the group of familial gastric cancer patients, particularly in patients diagnosed at less than 50 years of age (OR=3.687, p=0.0011) and females. The specific group of intestinal and mixed histopathological subtype occurs more frequently (OR=1.671) in consecutive carriers of I157T mutation. Recently, the NOD2/CARD15, gene located on chromosome 16q12, has been associated with Crohn’s disease. It is believed to play a role both in intracellular recognition of lipopolysaccharides (LPS) typical of Gram negative bacteria and subsequent activation of NFkB. 3020insC NOD2 mutation causes an increased risk of developing chronic inflammatory diseases of the gastrointestinal tract and colorectal cancer in their course. In light of recent studies, in fact 3020insC mutation predisposes to cancers of many organs, including breast, ovarian, lung. Studies conducted in our center in the group of 103 patients with a family history of gastric cancer, have shown that NOD2 3020insC carriers in persons over 50 y of age more than doubled (OR=2.479, p=0.022) and among women almost 3-fold increased risk. In addition, NOD2 R702W alteration occurred almost three times more frequently (OR=2.816, p=0.0121) in the group of 241 consecutive patients with gastric cancer diagnosed before 50 years of age and over 2-times frequently (OR=2.268, p=0.0371) in gastric cancer selected histopathologically as intestinal type according to Lauren. There are a large number of reports describing the relationship between changes in the gene TP53, particularly polimomorfizm Arg72Pro, and risk of gastric cancer. Many researchers have found links between gene polymorphism of Interleukin-1, and the risk of stomach cancer. Gene polymorphism of angiotensin converting enzyme ACE, was recently linked with the pathogenesis and development of human cancers. Research Ebert MP, et al. conducted in a group of 88 patients shows that the insertion / deletion ACE gene may be associated with the development of early gastric cancer in the German population. In the Japanese population genetically distant, however, found no relationship between gastric cancer and ACE gene polymorphism). Sentences on the ACE polymorphism and risk of stomach cancer researchers are divided among different centers. XRCC1 gene is part of composite protein complex containing the s-polymerase DNA ligase I and PARP (polymerase poly (ADP-ribose). This multi-unit complex is involved in DNA repair pathway. T. Poplawski et al. indicate that the variant Gln / Gln XRCC1 gene polymorphism Arg399Gly occurred more frequently in patients with gastric cancer and family burden (OR=2.04, 95% CI=1,27-3,29) and the results obtained from studies in the group of 152 patients with a family history of gastric cancer suggest that gene XRCC1 399Gln allele may be considered a marker of gastric cancer. In terms of predisposition to gastric cancer has also been studied recently LAPTM4B gene associated with a genetic predisposition to liver cancer, having LAPTM4B alleles * 1 and LAPTM4B * 2. The risk of stomach cancer was increased 1.819 times in patients with genotype * 1 / 2 (CI=1.273-2.601) and 2.387 times in patients with genotype * 2 / 2 LAPTM4B (CI=1.195-4.767) compared with genotype * 1 / first. These studies indicate that allele * 2 LAPTM4B may be one of the genetic factors of gastric cancer. Further studies of newly described mutation moderately increased risk of stomach cancer may allow to estimate the real risk of gastric cancer associated with these mutations in the Polish population.

Prognostic analysis of familial gastric cancer in Chinese population

The aim of this study was firstly to elucidate the prognosis of familial gastric cancer (FGC) in Chinese population. A total of 162 patients were recruited, including 81 patients with FGC and 81 patients with sporadic gastric cancer (SGC), who underwent gastrectomy between 1996 and 2007. Paraffin-embedded tumor specimens were obtained from tissue bank of Cancer Hospital, Fudan University. The expression of epidermal growth factor receptor (EGFR), P53, C-myc, and proliferating cell nuclear antigen (PCNA) were detected by immunohistochemical method. There were significant differences in tumor size, vessel invasion, EGFR, and P53 expression between FGC and SGC patients. The 5-year survival rates were 48% and 57% in FGC and SGC patients, respectively (P = 0.033). Subgroup analysis showed that the 5-year survival rates were worse in FGC patients with nerve invasion, high PCNA expression, negative expression of EGFR, and positive expression of P53 than those in SGC group. Multivariate analysis showed that AJCC stage, tumor size, and nerve invasion were independent prognostic factors in all patients. Furthermore, AJCC stage and P53 expression dramatically affected the prognosis of FGC patients. The prognosis of FGC patients might be worse than those of SGC patients. AJCC stage and P53 expression are independent prognostic factors in FGC patients.

Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer

Alterations of the cell adhesion molecule E-cadherin have been demonstrated in sporadic and hereditary gastric carcinomas. A cell adhesion molecule with functional similarity to E-cadherin is desmoglein 2 (Dsg2), a major component of the desmosomes. In this study, we investigated whether alterations of Dsg2 are involved in gastric carcinogenesis and whether germline mutations contribute to a genetic predisposition in familial gastric cancer patients with no germline mutations in the E-cadherin gene. Seventy-five formalin-fixed, paraffin-embedded tissues from 37 familial and 38 sporadic gastric carcinomas were analysed for Dsg2 expression by immunohistochemistry. DNA from 31 familial gastric cancer patients was analysed for germline mutations and five sporadic tumours were analysed for somatic mutations by DHPLC. Of the 75 tumours, 25 (33%) demonstrated abnormal (reduced and/or non-membrane-associated) Dsg2 expression. There was a trend towards more frequent abnormal expression in diffuse type (42%) than in intestinal type tumours (18%) (p = 0.066). One germline missense variant leading to a non-conservative amino acid change (c. 2810 C > A, Thr 937 Asn) was found in a familial gastric cancer patient with a diffuse type tumour. No somatic mutations were identified. The observed abnormal expression of Dsg2 protein suggests that this molecule is involved in the carcinogenesis of a subset of gastric carcinomas, in particular of the diffuse type. Somatic mutations in the gene do not seem to be a very frequent inactivation event and the finding of no clear pathogenic germline mutation rules out Dsg2 as a major gastric cancer predisposition gene.

The E-cadherin -347G->GA promoter polymorphism and its effect on transcriptional regulation.

E-cadherin plays a critical role in epithelial cell-cell adhesion and maintenance of tissue architecture. Loss of E-cadherin expression in humans has been associated with cancer, and a number of cancer-related mutations have been identified. Here, we sought to investigate whether the -347G-->GA single nucleotide polymorphism affects the transcriptional activity of the E-cadherin gene. First, we measured the promoter activity of the -347G-->GA polymorphism using a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The dual luciferase reporter assay showed that the GA allele decreased the transcriptional efficiency by 10-fold (P < 0.001) compared with the G allele. Similarly, EMSA revealed that the GA allele had a weak transcription factor binding strength compared with the G allele. We then examined the frequency of this polymorphism in familial gastric cancer (FGC) patients by denaturing high-performance liquid chromatography. We found that the E-cadherin genotype (-347G/GA heterozygous or GA homozygous) was associated with FGC patients (P < 0.05) compared with the G homozygous genotype. Taken together, these results suggest that the GA allele may cause weak transcription factor binding affinity and low transcriptional activity in E-cadherin expression.