Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non-cardia Gastric Cancer.

BACKGROUND: The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. METHODS: 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. RESULTS: MSI-H phenotype was found in 111 of 472 patients (23.5%). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6% vs. 35%, p < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95% CI 1.56-4.51, p < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet-ring cell/mucinous histotypes was observed. CONCLUSIONS: MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non-cardia tumors.

High incidence of familial gastric cancer in Tuscany, a region in Italy.

OBJECTIVES: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. METHODS: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. RESULTS: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). CONCLUSIONS: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.

Risk factors for liver metastases after curative surgical procedures for gastric cancer: a prospective study of 208 patients treated with surgical resection.

BACKGROUND: The aim of this study was to evaluate the risk of liver metastases after radical surgical treatment for gastric cancer, the potential risk factors involved, and the sensitivity of serum tumor markers during followup. STUDY DESIGN: A total of 208 patients who had undergone curative resection for primary gastric cancer and a prospective followup protocol were studied. The association between clinicopathologic variables and hepatic recurrence was investigated using standard univariate methods and multivariate Cox regression analysis. RESULTS: Mean followup time (+/- SD) for the entire patient population was 51 +/- 38 months (median 52 months) and was 88 +/- 24 months (median 81 months) for disease-free patients. Recurrence of gastric cancer was documented in 109 of 208 patients (52.4%). Liver metastases were found in 28 of 208 patients (13.5%); in most of these patients (82.1%) diagnosis was made within 2 years after surgical treatment. The estimated cumulative risk of liver metastases after 5 years was 16.4%. Cox regression analysis identified lymph node involvement (adjusted relative risk [RR] = 6.28, 95% confidence interval [CI] = 2.11 to 18.70, p = 0.001), preoperative positivity for CEA, CA 19-9, or CA 72-4 (RR = 5.18, 95% CI = 1.75 to 15.37, p = 0.003), and intestinal histotype (RR = 3.08, 95% CI = 1.06 to 8.96, p = 0.039) as independent predictors of hepatic recurrence. In 27 of 28 cases hepatic recurrence was associated with an increase in CEA, CA 19-9, or CA 72-4 serum levels above the cutoff, either before or at the time of the clinical diagnosis (sensitivity 96.4%). CONCLUSIONS: Preoperative positivity for serum tumor markers, lymph node involvement, and intestinal histotype are risk factors for liver metastases after radical surgical treatment for gastric cancer. Postoperative measurement of serum tumor markers may be useful for an early diagnosis of hepatic recurrence during followup.

CDH1 C-160A promoter polymorphism and gastric cancer risk.

The objective of this study was to find out whether C-160A single nucleotide polymorphism of the promoter region of the E-cadherin gene might be a potential genetic marker for identifying individuals at risk for gastric cancer (GC). To test this hypothesis, 412 GC patients and 408 controls were analyzed statistically. A PCR-restriction fragment length polymorphism assay was adopted for C-160A single nucleotide polymorphism detection. No statistical differences were found among CC, CA, and AA genotypes and the risk of GC, even stratifying according to age, sex, and area of residence. Similarly, genotype was not associated with intestinal or diffuse histotypes, or with cardia or noncardia carcinomas. In conclusion, the C-160A polymorphism is not associated with GC risk in the Italian population.

Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer.

BACKGROUND: Recent studies have suggested that Helicobacter pylori (H. pylori) infection may be related to better prognosis in patients with gastric cancer, but to the authors' knowledge, this finding has not yet been validated. In the current study, the association between H. pylori status and clinical outcome was investigated in a large cohort of patients. METHODS: Frozen non-neoplastic gastric mucosa and serum samples obtained from 297 patients who underwent surgery for primary gastric cancer between 1988 and 2004 were retrieved from the serum and tissue bank of the study department. H. pylori status was defined by means of polymerase chain reaction (PCR) analysis for the vacA gene in gastric mucosa and by serologic assay of H. pylori and CagA antibodies. Univariate and multivariate analyses were used for the association between clinicopathologic variables and long-term outcome. RESULTS: Positivity for H. pylori infection was observed in 256 of 297 patients (86%), whereas in 41 patients (14%), PCR for vacA and both serologic tests were negative. Negative H. pylori status was found to be significantly associated with cardia location, advanced pT classification, noncurative surgery, and a lower 5-year survival rate after R0 resection (24% vs 57%; P < .001). Multivariate survival analysis confirmed H. pylori status as a significant prognostic factor (hazards ratio, 2.47; 95% confidence interval, 1.40-4.35 [P = .002]). The influence of H. pylori status on long-term survival was observed in patients with early as well as advanced pT classifications. CONCLUSIONS: Negative H. pylori status appears to be an indicator of poor prognosis in patients with gastric cancer, and is independent of other well-known clinical and pathologic prognostic variables.