Prognostic significance of serum tumor markers in various pathologic subtypes of gastric cancer.

PURPOSE: This study aimed to assess the utility of 6 serum tumor markers in prognosis between gastric adenocarcinoma and gastric signet ring cell carcinoma (SRCC). METHODS: A cohort of 3131 cases of gastric adenocarcinoma and 275 cases of gastric SRCC was assembled. The serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125, alpha fetoprotein (AFP), carbohydrate antigen 242 (CA242), and carbohydrate antigen 724 (CA724) were measured in all cases. The study analyzed the association between the levels of these 6 tumor markers and the prognosis of gastric adenocarcinoma and SRCC. RESULTS: The study revealed that gastric SRCC exhibited lower concentrations of CEA (P < .001) and CA19-9 (P = .002), along with reduced positive rates of CEA (P = .041), CA19-9 (P = .003), AFP (P < .001), and CA242 (P = .006), while displaying higher positive rates of CA724 (P = .024) than gastric adenocarcinoma. Nevertheless, the receiver operating characteristic curve demonstrated that serum tumor markers did not hold clinical significance in differentiating between gastric adenocarcinoma and SRCC. Survival analysis substantiated that the combined criteria of serum tumor markers stood as an independent risk factor for both gastric adenocarcinoma and SRCC. Notably, the nomogram indicated that serum tumor markers exerted a more substantial influence on the prognosis of gastric adenocarcinoma than on gastric SRCC. CONCLUSION: The study concluded that the combined criteria of serum tumor markers emerge as independent risk factors for both subtypes of gastric cancer. Furthermore, this combined approach exhibited enhanced efficacy in prognosticating the outcome of gastric adenocarcinoma compared with gastric SRCC.

Preoperative Plasma Fibrinogen and Serum Albumin Score Is an Independent Prognostic Factor for Resectable Stage II-III Gastric Cancer.

BACKGROUND: Radical gastrectomy with D2 lymphadenectomy is recognized as the standard treatment for resectable advanced gastric cancer. Preoperative fibrinogen and albumin measurements may bring clinical benefits in terms of providing advanced notice of a poor prognosis or recurrence in patients undergoing radical resection. The aim of this study was to identify markers that are predictive of a poor prognosis prior to surgery. METHODS: Eight hundred forty-two consecutive patients who underwent curative radical gastrectomy at our hospital between 2008 and 2012 were retrospectively reviewed. Based on plasma fibrinogen and serum albumin levels, preoperative fibrinogen and albumin scores (Fib-Alb scores) were investigated, and the prognostic significance was determined. RESULTS: The patients were classified according to a Fib-Alb score of 0 (n = 376), 1 (n = 327), or 2 (n = 139). When the correlation between the response rate and the change in the Fib-Alb score was investigated, the response rate was significantly lower in patients with an increased Fib-Alb score than in the other patients. In the survival analysis, patients in the Fib-Alb high-score group exhibited significantly worse recurrence-free survival (RFS) (P = 0.030) than patients in the other groups. A multivariate analysis using clinical stage and the change in the Fib-Alb score as covariates revealed that a change in the Fib-Alb score (Fib-Alb score 1, HR: 1.31, 95% CI: 1.03-1.66, P = 0.028; Fib-Alb score 2, HR: 1.61, 95% CI: 1.20-2.17, P = 0.001) was a significant independent predictive factor for RFS. CONCLUSIONS: The prognosis of patients with high fibrinogen and low albumin levels is poor. The Fib-Alb score was shown to be an independent prognostic factor for postoperative recurrence in gastric cancer patients who underwent radical gastrectomy.

Unusually high levels of serum p53 antibody in recurrent gastric cancer.

Serum tumor markers in patients with cancer assist with establishing diagnosis, estimating prognosis, monitoring treatment, and detecting tumor recurrence. Changes in the p53 tumor suppressor gene are the most common genetic abnormalities in many different human malignancies. Several studies have demonstrated that serum p53 antibodies (S-p53Ab) comprise an early marker of malignant disease, a marker for treatment effects and a prognostic factor for patients with several types of tumors. We recently reported that S-p53Ab is useful for patients with gastric cancer. We describe a rare situation in which unusually high serum p53 antibodies helped to detect recurrent gastric cancer in the small intestine after gastrectomy. Further studies are required to gain a more precise understanding of the clinical impact of S-p53Ab titer monitoring in gastric cancer.

Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer.

BACKGROUND: Little is known about cytokine and angiogenic factors (CAFs) in gastric cancer (GC) in terms of tumor classification and prognostic value. Here, we aimed to correlate CAF signature with overall survival (OS) in GC. METHODS: We measured pretreatment serum levels of 52 kinds of CAFs in 68 GC patients who were treated with fluoropyrimidine and platinum combination chemotherapy using multiplex bead immunoassays and enzyme-linked immunosorbent assay. We evaluated correlations between CAF levels and pathological features and OS. RESULTS: Three distinct patient groups were identified: one with high levels of proangiogenic factors, another with high levels of proinflammatory factors, and the other with high levels of both factors. Eleven CAFs [interleukin (IL)-2 receptor-alpha, growth-regulated alpha protein, hepatocyte growth factor, macrophage colony-stimulating factor, stromal cell-derived factor, IL-6, IL-8, IL-10, interferon-gamma, vascular endothelial growth factor, and osteopontin] were independently correlated with poor OS. Clustering analysis of these 11 CAFs revealed distinct high and low 11-CAF signature groups. High 11-CAF signature was associated with shorter OS (10.1 vs. 17.9 months, p = 0.026) along with poor performance status, and the presence of signet ring cell components in multivariate analysis of OS (HR 1.76, p = 0.029). The patients' traditional clinicopathological characteristics were not significantly different between the high and low 11-CAF signature groups. CONCLUSION: Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies.

Prognostic implication of antitumor immunity measured by the neutrophil-lymphocyte ratio and serum cytokines and angiogenic factors in gastric cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is associated with a poor prognosis in many cancers but the biological mechanisms involved are unknown. Since cytokines and angiogenic factors (CAFs) are reflected by various immune responses, we analyzed the association between the NLR and CAFs and their prognostic implications in gastric cancer (GC). METHODS: Of 745 GC patients who were enrolled in NLR analysis, 70 underwent NLR and CAF association analyses. Pretreatment serum levels of 52 CAFs were measured by means of multiplex bead immunoassays and enzyme-linked immunosorbent assays. Linear regression analysis and survival analysis of the NLR with each CAF were performed. RESULTS: Metastatic organ numbers and carbohydrate antigen 19-9 levels were significantly higher in patients with a high NLR [greater than 2.42 (median): P = 0.047 and P < 0.001 respectively]. The overall survival was significantly worse in the high NLR group (17.8 months vs 11.2 months, P < 0.001). In CAF analysis, osteopontin (R 2 = 0.337, P < 0.001) and interleukin-6 (R 2 = 0.141, P = 0.001) were significantly associated with the NLR. Stromal-cell-derived factor 1 (SDF-1) was a significant poor prognostic factor independently of the NLR. Consideration of both the NLR and SDF-1 divided patient groups with different overall survival (both low, 21.0 months; either high, 15.8 months; both high, 8.2 months). CONCLUSION: The NLR is a significant poor prognostic factor in advanced GC. The NLR is mainly associated with osteopontin and interleukin-6. Besides the NLR, SDF-1 is an independent poor prognostic factor in GC. Consideration of both the NLR and SDF-1 might give insights into antitumor immunity in GC.

High circulating tumor cell concentrations in a specific subtype of gastric cancer with diffuse bone metastasis at diagnosis.

AIM: To clarify the biological feature contributing to gastric cancer with diffuse bone metastases at diagnosis. METHODS: The participants visited the Department of Clinical Oncology, Akita University Hospital, from January 2014 to August 2015. The selection criterion for gastric cancer with diffuse bone metastases at diagnosis includes over 29 hot spots of bone scintigraphy. Circulating tumor cell were collected from 20 mL of peripheral venous blood drawn using a CellSearch kit and a CellTracks AutoPrep system by SRL, a clinical laboratory. The endpoints of this study were correlations between circulating tumor cells (CTC) count and therapeutic outcomes. RESULTS: Among 39 patients with gastric cancer, 5 patients met the criterion. The incidence of this subtype was 12.8%. CTC counts ranged from 235 to 6440 cells/7.5 mL of peripheral blood (median of 1724). These values were much higher than common gastric cancers (2 cells). In chemo-sensitive cases, CTC counts decreased within 14 d (median) from 275, 235 and 1724 to 2, 7 and 66, respectively. On the other hand, CTC counts increased after treatment failure or insensitive case from 2, 7 and 6440 to 787, 513 and 7885, respectively. The correlation between CTC count and survival time showed a trend, but did not reach significance (Y = 234.6 - 0.03X, P = 0.085). CONCLUSION: High CTC count is a biological hallmark of this subtype, and can be used as a direct and definitive indicator of therapeutic outcome.

High levels of platelet/lymphocyte ratio are associated with metastatic gastric cancer.

PURPOSE: The predictive and prognostic value of cheap, easily accessible and commonly available complete blood count parameters has already been studied in a variety of cancers. In the present study, we aimed to investigate the association between pretreatment platelet/lymphocyte ratio (PLR) and metastatic gastric cancer. METHODS: The records of 228 patients dating from January 2010 to June 2014 were retrospectively evaluated. Patients who had undergone radical (N=157) or palliative gastrectomy (N=71) for metastatic gastric cancer were included and divided into two groups according to stage (early-advanced) and metastasis (absence-presence) status, and PLR values were compared. RESULTS: 38 (16.6%) of 228 patients had early gastric cancer (non metastatic cases). PLR values of advanced gastric cancer (not including metastatic cases) were significantly higher compared to early gastric cancer (231.6±107.45 and 160.3±71.5, respectively; p<0.001). Seventy one (31.1%) of 228 patients had distant metastasis. PLR values of metastatic gastric cancer were significantly higher than in non-metastatic gastric cancer (251.0±94.8 and 192.7±88.8, respectively; p<0.001). Logistic regression analysis showed that PLR was an independent predictive factor for tumor burden in both stage and metastasis groups (p<0.001 and p=0.003, respectively). Also, in correlation analysis, PLR showed mild correlation with stage and metastasis groups (r=0.291 and r=0.299, respectively). CONCLUSIONS: Pretreatment PLR values were correlated with tumor burden, and most higher values were detected in metastatic disease. Our findings may be useful, especially in the decision-making for laparoscopic staging in patients who have no radiological evidence of metastatic disease.

Preliminary evaluation of clinical utility of CYFRA 21-1, CA 72-4, NSE, CA19-9 and CEA in stomach cancer.

BACKGROUND: Although various tumor markers have been utilized in management of stomach cancer (SC), only a few reports have described relevance of examples such as CYFRA 21-1 and neuron-specific enolase (NSE). The purpose of this study was to evaluate the potential diagnostic performance of carcinoembryonic antigen (CEA), CA 19-9, CA72-4, CYFRA 21-1 and NSE in patients with SC. MATERIALS AND METHODS: Ninety-six SC patients with pathologic confirmation between 2012 and 2013 were enrolled. Serum levels of five tumor markers were analyzed using a solid-phase immunoradiometric assay. Receiver operating characteristic (ROC) curves were plotted for the five tumor markers to investigate their diagnostic powers and adjusted cutoff values derived from analysis of ROC curves were evaluated to calculate the sensitivity of each for SC with recommended cutoff values. RESULTS: Based on two different cutoff values (recommended and adjusted), CYFRA 21-1 (≥2.0 and 1.2 ng/ml) had a respective sensitivity of 50% and 78.1%, compared with 8.3% and 18.8% for CEA (≥7.0 and 3.9 ng/ml), 15.6% and 18.8% for CA 19-9 (≥37 and 26.7 ng/ml), 28.1% and 9.6% for CA 72-4 (≥4.0 and 13 ng/ml) and 7.3% and 7.3% for NSE (≥14.7 and 15.0 ng/ml) in the initial staging of primary SC. The area under the curve (AUC) for CYFRA 21-1, with a value of 0.978 (95% confidence interval, 0.964-0.991) was comparatively the highest. Univariate analysis revealed significant relationships between tumor marker level and lymph node involvement, metastasis and staging with CYFRA 21-1, CA 72-4 and NSE. CONCLUSIONS: CYFRA 21-1 was the most sensitive tumor marker and showed the most powerful diagnostic performance among the five SC tumor markers. NSE and CA 72-4 are significantly related to lymph node involvement, metastasis or stage. Further evaluations are warranted to clarify the clinical usefulness and prognostic prediction of these markers in SC.

Evaluating the significance of expression of CEA mRNA and levels of CEA and its related proteins in colorectal cancer patients.

OBJECTIVE: To explore the clinical significance of expression of CEA mRNA and serum CEA and the related proteins in colorectal cancer (CRC). METHODS: Blood samples were collected from 370 CRC patients and 350 controls. CEA mRNA was determined by RT-PCR and levels of CEA, CA19-9, CA242, and CA724 were examined with chemiluminescence. RESULTS: The positive rate of jointly detecting serum CEA, CA19-9, CA242, and CA724 was significantly higher than CEA mRNA expressions (P < 0.01), both positive rates were significantly correlated with TNM stage, lymph node, and visceral metastasis. The positive rate of jointly detecting in patients with poorly differentiated tumor was significantly higher than that in patients with highly differentiated tumor (P < 0.01). By contrast, CEA mRNA expression was not related with histopathologic grading. Postoperative follow-up found that all patients with high levels of CEA mRNA and serum CEA and the related proteins had liver, lung, pelvis, or other distant metastases. CONCLUSIONS: These results suggest that high expressions of CEA mRNA and high levels of serum CEA and the related proteins are associated with the incidence and advanced of CRC. In addition, joint detection of serum CEA and the related proteins is more sensitivity than examination of serum CEA mRNA.

The prognostic significance of the increase in the serum M30 and M65 values after chemotherapy and relationship between these values and clinicopathological factors in patients with advanced gastric cancer.

In some studies, the prognostic and predictive significance of M30 and M65 has been reported to detect response to chemotherapy. In the present study, we aimed at determining the changes of serum M30 and M65 values after chemotherapy and the impact of these values on treatment response and progression-free survival (PFS) and overall survival (OS) of patients with advanced gastric cancer. A total of 31 patients with advanced gastric cancer was included. M30 and M65 values were measured by a quantitative enzyme-linked immunosorbent assay (ELISA) method in serum samples before and 48 h after the first chemotherapy cycle. Pre- and postchemotherapy values of M30 and M65 were compared. The difference between the mean values of serum M30 and M65 before and after chemotherapy was calculated and the prognostic significance of changes for survival was evaluated by univariate and multivariate analysis. Logistic regression analysis was performed to predict response to chemotherapy. Serum M30 and M65 levels were found to be increased significantly after chemotherapy (M30, 582.7 ± 111.5 U/l [pre mean] vs. 983.3 ± 214.1 U/l [post mean], p = 0.01; M65, 2,061.7 ± 431.2 U/l [pre mean] vs. 2,646.3 ± 433.1 U/l [post mean], p = 0.003). Means of the differences of M30 and M65 levels before and 48 h after chemotherapy were 400.5 ± 190 U/l ([M30-difference] M30-D) and 584.6 ± 335.4 U/l (M65-D), respectively. Patients with serum M30-D of <400.5 U/l had better median PFS and OS times than patients with M30-D >400.5 U/l (PFS, 9.9 vs. 4.3 months, p = 0.018 and OS, 13.6 vs. 8.1 months, p = 0.029). In addition, median PFS and OS intervals in patients with serum M65-D > 584.6 U/l were significantly worse than those of patients whose M65-D was lower than or equal to 584.6 U/l (4.1 vs. 11.4 months for PFS, p = 0.002 and 5.7 vs. 13.6 months for OS, p = 0.005). Patients with values above M30-D and M65-D had a better tumor response compared with patients with values below M30-D and M65-D (p = 0.02 and p = 0.006, respectively). In the logistic regression analysis, only M65-D was significantly found to be an independent factor in predicting response to chemotherapy (p = 0.018, OR:1.4). However, only M30 levels after chemotherapy were found to be an independent prognostic factor for PFS in the multivariate analysis. These results showed for the first time that both M30 and M65 in serum samples of patients with advanced gastric cancer were elevated 48 h after chemotherapy and these were poor prognostic factors for both PFS and OS of patients. Moreover, increased serum M65 levels after chemotherapy can be predict tumor response.

Expression and prognostic significance of CEACAM6, ITGB1, and CYR61 in peripheral blood of patients with gastric cancer.

BACKGROUND: We examined CEACAM6, ITGB1, and cyr61 concentrations from patients with gastric cancers (GCs) to assess their clinical application for diagnosing and monitoring diseases. METHODS: Real-time reverse transcription-polymerase chain reaction was used to detect the expressions of CEA, CEACAM6, ITGB1, IGF1R, CK20, cyr61, and S100A4 in peripheral blood karyocyte from 82 patients with GC, 24 patients with recurrence, and 37 healthy volunteers. Receiver operating characteristics (ROC) curves were constructed. RESULTS: There were significant association between these CEACAM6, ITGB1, and cyr61 and TNM Stages and distant metastasis. The AUC of CEACAM6 was 0.884 ± 0.044 (P = 0.0001), the AUC of cyr61 was 0.833 ± 0.047 (P = 0.0001), and the AUC of ITGB1 was 0.838 ± 0.042 (P = 0.0001) by differentiating preoperative GC patients from healthy volunteers from ROC curve analysis. The AUC of CEACAM6 was 0.761 ± 0.066 (P = 0.001), the AUC of CYR61 was 0.762 ± 0.063 (P = 0.001), and the AUC of ITGB1 was 0.824 ± 0.051 (P = 0.0001), by differentiating recurrence of GC from healthy volunteers from ROC curve analysis. CONCLUSION: The method of detecting the expression of CEACAM6, ITGB1, and CYR61 in peripheral blood of GC patients was more sensitive than CEA, IGF1R, CK20, and S100A4 for the early diagnosis of metastasis and recurrence.

Prognostic significance of serum vascular endothelial growth factor per platelet count in unresectable advanced gastric cancer patients.

OBJECTIVE: Angiogenesis is one of the crucial steps in various solid tumor growth and metastasis. However, there are limited data regarding the clinical and prognostic significance of serum vascular endothelial growth factor levels per platelet count in unresectable advanced gastric cancer compared with early gastric cancer and healthy volunteers. METHODS: A total of 181 gastric cancer patients were included and control serum samples were acquired from 113 healthy volunteers. The levels of serum vascular endothelial growth factor were measured using human vascular endothelial growth factor quantitative enzyme-linked immunosorbent assay. Survival curves were calculated using the Kaplan-Meier method and survival comparisons were made by the log-rank test in metastatic gastric cancer. RESULTS: There was a significant correlation between serum vascular endothelial growth factor levels and differentiation of tumor (P = 0.014), stage (P = 0.036). The overall survival (P = 0.0432) and the progression-free survival (P = 0.0116) were significantly shorter in patients with high serum vascular endothelial growth factor per platelet count (≥1.626 pg/10(6)). In the multivariate analysis, the presence of peritoneal carcinomatosis (P = 0.039), serum vascular endothelial growth factor per platelet (P = 0.005) were found to be significantly associated with poor progression-free survival. CONCLUSIONS: This study demonstrates that serum vascular endothelial growth factor per platelet count is correlated with poor overall survival and progression-free survival in patients with advanced gastric cancer.

The potential for serum p53 to predict the response to chemotherapy of patients with gastric cancer.

This study was designed to investigate the relationship between serum p53, tissue p53 and tissue permeability glycoprotein (P-gp) levels in gastric cancer. Serum levels of p53 were detected by enzyme-linked immunosorbent assay, and tissue p53 and P-gp levels were analysed by immunohistochemistry. In total, 63.0% of gastric cancer tissue samples tested positive for P-gp and 58.7% of samples tested positive for p53. Tissue P-gp immunoreactivity was significantly correlated with tissue p53 immunoreactivity, and both tissue p53 and P-gp immunoreactivity were significantly correlated to the degree of cancer cell differentiation. The percentage of gastric cancer patients with serum positive for p53 was 36.2%, which was significantly higher than the rate in non-cancerous gastric disease patients. Serum p53 was significantly correlated to tissue p53 and tissue P-gp, inferring that the presence of p53 in the serum could indicate the status of tissue p53 and P-gp. This could, therefore, be useful for screening for the most appropriate (lowest toxicity and highest effectiveness) drugs to use ahead of (neo)-adjuvant chemotherapy.

Primary signet-ring cell adenocarcinoma of the endometrium: case report and review of the literature.

Endometrial adenocarcinoma presenting with deep venous thrombosis is an exceptional event more typical of extra-mullerian primary tumors. Metastases to the spleen are also unusual in this setting. In addition, primary endometrial adenocarcinoma with signet-ring cell features has been reported only once. This study describes a case of primary endometrial carcinoma with prominent signet-ring cell features that presented in an unusual manner: with bilateral deep vein thromboses and splenic metastases. It is important for clinicians and pathologists to be aware of this entity; it may have an atypical clinical presentation and the histologic features raise a spectrum of differential diagnoses.

Thrombotic thrombocytopenic purpura as the first manifestation of metastatic adenocarcinoma in a young woman.

Thrombotic microangiopathy occurs in 5-10% of patients with mucin-producing disseminated adenocarcinoma. A 28-year-old woman complained of fatigue, bone pain, and weight loss. There were pallor, icterus, and tenderness in the bones on physical examination. Microangiopathic hemolytic anemia, leukoerythroblastic picture, thrombocytopenia, and normal coagulation tests were detected. Thrombotic thrombocytopenic purpura (TTP) was diagnosed and therapeutic plasma exchange was performed on the patient. On day 5 a laparotomy had to be performed because of acute abdomen due to the rupture of a corpus hemorrhagicum follicle of an ovary. Signet ring cell adenocarcinoma stained with cytokeratin 7 and mucicarmine was seen on ovaries and bone marrow, after the pathological examination. The primary site of tumor could not be investigated, because of the patient's refusal. Although chemotherapy including cis-platinum, infusional 5-fluorouracil, and calcium leucovorin were administered in two courses, she died from respiratory failure. In conclusion, malignancy and bone marrow involvement should be considered when associated with leukoerythroblastic picture and TTP.

Serum carcinoembryonic antigen monitoring after curative resection for colorectal cancer: clinical significance of the preoperative level.

AIM: We evaluated preoperative serum carcinoembryonic antigen (CEA) as a prognostic factor for colorectal cancer and determined when surveillance of this marker was useful. METHODS: Serum CEA was measured preoperatively in 1,263 patients who underwent curative resection for colorectal cancer at 3-month intervals for the first 2 postoperative years and at 6-month intervals thereafter. Mean follow-up was 48 months (range 1-156 months). RESULTS: The 5-year disease-free survival was less in patients with a high preoperative serum CEA level (P<0.0001). Among patients with a tumor recurrence, 38.5% had high follow-up serum CEA levels. The number of patients with high postoperative serum CEA levels exceeded the number of patients with high preoperative levels. High preoperative and follow-up serum CEA levels were independent prognostic factors for tumor recurrence (P=0.003 and P<0.001, respectively). In patients with high preoperative serum CEA levels, CEA surveillance had a 92.3% positive predictive value (PPV) and a 96.1% negative predictive value (NPV). The mean interval between postoperative serum CEA elevation and the diagnosis of a tumor recurrence [diagnostic interval (DI)] was 2.5 months (range 5-17 months). The DI was 0 in 18.8% of patients with a tumor recurrence. CONCLUSION: High serum CEA levels preoperatively and at follow-up are prognostic factors for colorectal cancer. Postoperative serum CEA surveillance is used most effectively when patients have high preoperative serum CEA levels. Considering the DI of 0 in 18.8% of the patients, the current CEA surveillance schedule might be changed.

Reprimo as a potential biomarker for early detection in gastric cancer.

PURPOSE: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary. EXPERIMENTAL DESIGN: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2'-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age- and gender-matched controls (validation group). RESULTS: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK, and p16). Eight genes (BRCA1, p73, RARbeta, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001). CONCLUSION: Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.