Biomarker For Early Gastric Cancer Research Articles

CAPG is a novel biomarker for early gastric cancer and is involved in the Wnt/β-catenin signaling pathway

Past studies have shown that the Gelsolin-like actin-capping protein (CAPG) regulates cell migration and proliferation and is strongly associated with tumor progression. We present the first study of the mechanism of action of CAPG in early gastric cancer (EGC). We demonstrate that CAPG expression is upregulated in gastric cancer (GC) especially EGC. CAPG promotes GC proliferation, migration, invasion, and metastasis in vivo and in vitro. More importantly, CAPG plays a role in GC by involving the Wnt/β-catenin signaling pathway. Our findings suggest that CAPG may function as a novel biomarker for EGC.

EpCAM is a new potential serum biomarker for early gastric cancer

EpCAM is a new potential serum biomarker for early gastric cancer

P-260 Plasma exRNA-based identification of novel biomarkers in early gastric cancer

Since early gastric cancer rarely causes symptoms, there are still many challenges in early detection. So far, there is no ideal biomarker for early Gastric Cancer (EGC) screening. We attempted to use circulating extracellular RNA markers combined with bioinformatics techniques to explore effective and non-invasive biomarkers for detection of early gastric cancer.

Integrating SWATH-MS Proteomics and Transcriptome Analysis Identifies CHI3L1 as a Plasma Biomarker for Early Gastric Cancer

Early diagnosis of gastric cancer (GC) provides patients opportunities for minimally invasive endoscopic resection. Here, we developed a new strategy integrated the state-of-the-art sequential windowed acquisition of all theoretical fragment ion (SWATH) mass spectra (MS) with multi-dataset joint analysis to screen for the stage-I GC plasma biomarker. In SWATH-MS assays, we identified 37 upregulated and 21 downregulated proteins in GC plasma. In the mRNA database analysis, 633 genes were identified as differentially expressed genes in at least 4 out of 5 datasets, but there were only 94 genes identified as upregulated. Only 1 gene, CHI3L1, was characterized as upregulated in both the dataset consensus list and the SWATH-MS list. Then, we detected the CHI3L1 level in the plasma of a large cohort consisting of 200 participants. The area under the ROC curve (AUC) of CHI3L1 in distinguishing GC from others was 0.788. Integrating the plasma CHI3L1 level with clinical factors further boosted the AUC to 0.887. In conclusion, we provide a novel strategy for biomarker screening, combining recent MS techniques with public database analysis, and identified plasma CHI3L1 as a potential biomarker for patients with endoscopically resectable GC.

S100A9 as a novel diagnostic and prognostic biomarker in human gastric cancer

Objective: The morbidity and mortality of gastric cancer (GC) is high, but there are lack of the biomarkers for early diagnosis and progression of GC. We aimed to identify a novel biomarker for the growth and progression of GC.Methods: The Cancer Genome Atlas (TCGA) database including 352 eligible patients was used to screen candidate genes related to the prognosis of GC. A proteomics analysis of Chinese Human Proteome Sketches (CHPS) including 84 eligible sample tissues was conducted to further identify candidate biomarkers. A series of in vitro assays were performed to investigate the functions of candidate proteins in GC. Next, to verify whether the candidate oncogene was associated with gastric carcinogenesis, we screened its expression levels using samples from 200 patients with chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia, or GC and healthy controls.Results: According to the analyses of the TCGA database and CHPS, we found that S100A9 may be associated with the prognosis of GC. The results of proliferation, wound-healing and invasion assays, immunohistochemistry (IHC) and western blot showed that high levels of S100A9 in tissues were significantly associated with GC aggressiveness and a poor prognosis (p < .05). Furthermore, we found that the expression of S100A9 increased gradually during the process of gastric carcinogenesis (p < .05). The diagnostic sensitivity and specificity of S100A9 as a biomarker for early GC were 61.4% and 81.3%, respectively.Conclusions: This study reveals that S100A9 may be a novel biomarker for the early diagnosis and prognosis of GC patients.

Circular RNA hsa_circ_0006848 Related to Ribosomal Protein L6 Acts as a Novel Biomarker for Early Gastric Cancer.

Objective Circular RNAs (circRNAs) have been reported to be widely involved in pathological processes of various cancers. However, little is known about their diagnostic values in early gastric cancer (EGC). This study is aimed at exploring whether circulating circRNAs in plasma could act as biomarkers for EGC diagnosis. Materials and Methods Mass spectrometry (MS) was performed to identify the proteins that at significantly aberrantly levels in gastric cancer (GC) tissues. The target circRNA was identified by bioinformatics analysis. A receiver operating characteristic (ROC) curve was generated to evaluate the diagnostic utility. Results MS revealed that the ribosomal protein L6 (RPL6) expression was significantly downregulated only in EGC tissues vs. nontumorous tissues; this was validated by western blotting (n = 30, p = 0.0094). Bioinformatics analysis predicted that there is a hsa_circ_0006848/hsa_miR-329-5p/RPL6 axis in GC progression. The hsa_circ_0006848 expression was significantly downregulated in EGC tissues (vs. nontumorous tissues, n = 30, p = 0.0073) and plasma samples from EGC patients (vs. paired healthy volunteers, n = 30, p = 0.0089). In addition, the hsa_circ_0006848 plasma level in postoperative patients was significantly higher than that of preoperative patients (n = 30, p = 0.047). Furthermore, the decreased hsa_circ_0006848 expression in plasma was negatively correlated with poor differentiation (p = 0.037) and tumor size (p = 0.046). The area under the ROC curve (AUC) of hsa_circ_0006848 in plasma was 0.733, suggesting a good diagnostic value. The plasma hsa_circ_0006848 level combined with the carcinoembryonic antigen (CEA), carbohydrate-associated antigen 19-9 (CA19-9), and carbohydrate-associated antigen 72-4 (CA72-4) level increased the AUC to 0.825. Conclusion Our results indicated that plasma hsa_circ_0006848 may be a novel noninvasive biomarker in EGC diagnosis.

Abstract 5395: MicroRNA-196b-3p identified from serum microRNA expression profiling is a potential diagnostic biomarker for gastritis and early gastric cancer

Abstract Background: Gastric cancer is one of the most common forms of cancer worldwide. The progression of chronic atrophic gastritis (CAG) is involved in gastric carcinogenesis. With the progression of chronic atrophic gastritis, the risk of gastric cancer increased in a stepwise fashion. Non-invasive tools for early gastric cancer are required to improve the prognosis. MicroRNAs (miRNAs), a class of small non-coding RNAs of 19-22 nucleotides in length, function as post-transcriptional regulators by directly cleaving target messenger RNA or translational repression. MiRNAs in serum have been shown to be potential biomarkers in various type of cancers and several miRNAs have been reported in gastric cancer. The purpose of present study was to identify a serum miRNA expression profile that can serve as a novel diagnostic biomarker for early gastric cancer. Materials and Method: We defined a normal gastric mucosa as grade0, CAG classified C-1, 2 in Kimura-Takemoto classification as grade1, CAG classified C-3, O-1 in Kimura-Takemoto classification as grade2, and CAG classified O-2, 3 in Kimura-Takemoto classification as grade3. We obtained 344 serum samples, which gathered from 19 health people (grade0), 125 patients with chronic atrophic gastritis (grade1: 54, grade2: 36, grade3: 35), and 200 patients with early gastric cancer. The miRNAs were extracted from serums and miRNA microarray analysis was performed. In the discovery phase, we analyzed 71 cases (grade0: 11, grade1: 20, grade2: 20, grade3: 20). Next, in the training phase, we analyzed 73 cases (grade0: 8, grade1: 34, grade2: 16, grade3: 15). Then, we analyzed 200 early gastric cancer serum samples. Result: The microarray analysis identified a profile of miRNA (miRNA-196b-3p) as a biomarker for early gastric cancer. The analysis results showed that the expression level of the serum miRNA was correlated to degree of CAG and carcinogenesis. When compared with grade0,1,2 and grade3, the area under the receiver operating characteristic (ROC) curve of this serum miRNA signature was 0.730 and 0.763 for the two sets of serum samples. There was significant difference in serum value of miRNA-196b-3p between grade1-3 and early gastric cancer (p=0.003). Conclusion: Serum miRNA-196b-3p is good biomarker for early gastric cancer. Citation Format: Atsushi Fujii, Sho Nambara, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Takaaki Masuda, Takao Otsuka, Masafumi Nakamura, Koshi Mimori. MicroRNA-196b-3p identified from serum microRNA expression profiling is a potential diagnostic biomarker for gastritis and early gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5395.

CEACAM6 is upregulated by Helicobacter pylori CagA and is a biomarker for early gastric cancer.

Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro. The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro, a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach.

Abstract 546: CD44 variant expression is a poor prognostic marker in early gastric cancer and well-differentiated gastric cancer

Abstract The present study is to investigate the significance of the expression of CD44 variant (CD44v), a functional cancer stem cell marker, in the primary gastric cancer. We first tested whether CD44v is selectively expressed in gastric cancer tissue. With the tissue microarray samples containing the 6 normal tissue, 6 H. pylori associated gastritis, 12 intestinal metaplasia, 12 low-grade adenoma, 12 high-grade adenoma, 25 early gastric cancer and 26 advanced gastric cancer. The positive expression rates in tumor were 65.3% (49/75) whereas the positive rates in normal and gastritis tissue were 30.4% (p = 0.003). Next, we investigated the clinical significance of gastric cancer with the tissue microarray containing 333 gastric cancer tissue derived from the patients who underwent radical gastrectomy for gastric cancer from 1999 to 2007. The positive expression rates of CD44v (55%, 134/242) were higher in intestinal type gastric cancer than in diffuse type (28%, 21/76). Intestinal type gastric cancer among the CD44v-positive gastric cancer accounted for 82% (134/164). The 5-year survival rate of CD44v-positive gastric cancer was 67.7% whereas that of CD44v-negative gastric cancer was 62.9%. The survival difference was higher as time passed, but it was statistically insignificant (p = 0.219). However, in the subgroup analysis we found that the survival differences were significantly higher in early gastric cancer and well-differentiated gastric cancer (p = 0.013, 5-YSR ; p = 0.046, 5-YSR , respectively). We also investigated the correlation between the expressions of CD44v and EGFR along with the well-known proliferative molecular biomarkers, cylin D1 and Ki-67. Only the expression of Ki-67 were some correlation with CD44v expression in gastric cancer; CD44v-positive rates of the cancers with negative or 1 positive Ki-67 expression were 37% (47/127) whereas those with 2 or 3 positive Ki-67 expression were 57.4% (116/202). This study demonstrates that CD44v can be a good biomarker for early gastric cancer and well-differentiated gastric cancer. [This study was supported by a grant from the National R&amp;D Program for Cancer Control, Ministry for Health, Welfare &amp; Family Affairs, Republic of Korea. (0820050).] Citation Format: Won Sup Lee, Se-Il Go, Jeong-Hee Lee, Sang-Ho Jeong, Young-Joon Lee, Soon Chan Hong, Woo Song Ha, Gyung Hyuck Ko. CD44 variant expression is a poor prognostic marker in early gastric cancer and well-differentiated gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 546. doi:10.1158/1538-7445.AM2014-546

A two-microRNA signature as a potential biomarker for early gastric cancer

Gastric cancer (GC) is one of the most common malignant tumors worldwide. No fundamental improvements in the five-year survival rates of patients with GC have been reported due to a low early diagnosis rate. Therefore, the identification of novel biomarkers is urgently required for an early diagnosis of GC. A total of 86 patients were selected for the present study, including 44 patients with early stage GC (T1–T2 according to TNM staging criteria) and 42 normal gastric mucosa samples from non-cancer patients as controls. A total of 18 samples were used for the microRNA (miRNA) microarray experiments, including nine early GC and nine normal gastric mucosa samples. Bioinformatics algorithms, significant analysis of microarray (SAM), top scoring pair (TSP) and statistical receiver operating characteristic curves were used to identify the best signatures. Finally, quantitative PCR was used to validate the candidate biomarkers for early gastric cancer in the test samples (35 cancer and 33 normal samples). Using the SAM algorithm, 14 differential miRNAs were selected as candidate biomarkers. Using the TSP algorithm, hsa-miR-196a and hsa-miR-148a were obtained as a signature to differentiate between the early GC and normal samples. A coincidental result was observed in the test samples. hsa-miR-196a was upregulated and hsa-miR-148a was downregulated in the early GC samples. hsa-miR-196a and hsa-miR-148a have the potential to serve as candidate biomarkers for early GC.

MiRNA‐199a‐3p: A potential circulating diagnostic biomarker for early gastric cancer

Tumor-associated miRNAs have been detected in serum or plasma. We investigated whether plasma miRNA-199a-3p could be a potential circulating biomarker for early gastric cancer (EGC). By using real-time qRT-PCR, the expression of miRNA-199a-3p were compared between these pre-operative plasmas from 30 EGC patients and 70 healthy controls, and between these pre-operative and post-operative plasmas. Further validation was on an independent set of plasmas from 50 EGC patients. The expression of miRNA-199a-3p (47.5 ± 6.5) in plasma in EGC patients was significantly higher than that from healthy controls (13.9 ± 2.7, P < 0.001) and gastric precancerous diseases (GPD) patients (19.2 ± 2.5, P = 0.004), respectively. Furthermore, the expression levels of miRNA-199a-3p (11.8 ± 2.9, P = 0.012) in the post-operative plasmas were significantly reduced when compared to the pre-operative plasmas. With respect of clinicopathological characteristics, the expression of miRNA-199a-3p in plasma was not associated with the depth of tumor invasion. Moreover, the AUC of the expression of miRNA-199a-3p in plasma for EGC diagnosis was 0.818, which was significantly higher than that of combined tumor markers (0.556). The sensitivity, specificity and accuracy of miRNA-199a-3p expression in plasma for EGC diagnosis were 76%, 74%, and 75%, respectively. Plasma miRNA-199a-3p could be a novel potential diagnostic biomarkers for EGC.