Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples

Abstract

Endoscopic biopsy prior to chemotherapy provides an opportunity for studying biomarkers to predict the overall survival in gastric cancer patients. This prospective study was performed to identify prognostic biomarkers in patients with unresected gastric cancer. Fifty-nine cases of chemotherapy-naive metastatic gastric cancer were enrolled in this study. A microarray analysis was performed using 40 biopsy samples to identify candidate genes whose expressions might be correlated with the overall survival. After adjusting for clinical covariates based on a multivariate analysis, the identified genes were validated using real-time reverse transcription polymerase chain reaction (RT-PCR) analysis in 19 independent validation samples. Ninety-eight candidate genes whose expression levels were significantly correlated with the overall survival were identified using a microarray analysis based on a proportional hazards model (P < 0.005). Multivariate analysis was performed to assess 10 of these genes, and the results yielded a statistical significance level for DACH1 and PDCD6. We further evaluated these two genes in independent samples using real-time RT-PCR and found that lower mRNA expression levels of PDCD6 were correlated significantly with a poor overall survival. We identified PDCD6 as a prognostic biomarker in patients with unresected gastric cancer using endoscopic biopsy samples. O ver the past two decades, various anticancer agents have been examined for their efficacy against gastric cancer, including 5-fluorouracil (5-FU) and 5-FU-based drugs, taxanes, CPT-11 and cisplatin, all administered either as monotherapy or in combination regimens;(1) however, the median survival time (MST) of these patients remains at only approximately 7 months.(2,3) In a recent randomized phase III trial examining oral S-1 monotherapy and cisplatin plus irinotecan combination therapy, the response rates to both S-1 and to the cisplatin plus irinotecan combination therapy were approximately 50%, indicating that around half of the patients did not respond to chemotherapy, (4)(5)(6)(7) and the MST in both the arms was less than 1 year.(8) Thus, the prognosis of patients with gastric cancer remains poor.The commonly recognized prognostic factors in cases of unresectable gastric cancer are the performance status, presence/ absence of liver metastases, presence/absence of peritoneal metastases and the serum levels of alkaline phosphatase.(9) Many molecular biomarkers have been also investigated for their potential to predict the outcome in hypothesis-based studies. Several studies have shown that the mRNA levels and immunohistochemical staining intensity of thymidylate synthase (TS) in gastric cancers treated with fluorouracil are associated with the response and survival; in addition, the excision repair crosscomplementing (ERCC)1 gene expression level has been shown to be associated with the clinical outcome in patients treated with cisplatin.(10,11) HER2 expression has also been reported to be a prognostic marker in cases of differe...

mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells

“…The methods were previously described (9). The primers used for the real-time reverse transcription-PCR (RT-PCR) were as follows: CD133, forward 5 ¶-AGT GGC ATC GTG CAA ACC TG-3 ¶ and reverse 5 ¶-CTC CGA ATC CAT TCG ACG ATA GTA-3 ¶; glyceraldehyde-3-phosphate dehydrogenase (GAPD), forward 5 ¶-GCA CCG TCA AGG CTG AGA AC-3 ¶ and reverse 5 ¶-ATG GTG GTG AAG ACG CCA GT-3 ¶.…”

“…The mRNA expression levels of CD133, HIF-1a, and HIF-1h in gastric cancer specimens were obtained from previously published microarray data (9).…”

Transcription Elongation Regulator 1 Is a Co-integrator of the Cell Fate Determination Factor Dachshund Homolog 1

“…Vertebrate homologs of ey (Pax6), so (Six), eya (Eya), and dac (DACH1) have been identified, and the human DACH1 (Dach1 in mice) gene encodes a protein composed of two highly conserved domains, dachshund domain 1 (DD1, also known as Box-N) with a predicted helix-turn-helix structure, and dachshund domain 2 (DD2, also known as Box-C). Altered expression of DACH1 has been reported in a variety of human tumors (5)(6)(7)(8)(9). DACH1 is expressed widely in normal epithelial tissues, and reduced DACH1 expression predicts poor outcome of breast and endometrial cancer patients (6,9).…”

What Can and Cannot Be Done Using a Microarray Analysis? Treatment Stratification and Clinical Applications in Oncology

“…[13][14][15] We previously used microarray analyses to identify prognostic biomarkers for gastric cancer using endoscopic biopsy samples. 16) Retrospective gene expression analyses of clinical samples revealed that several gastric cancers overexpressed EGFR, HER2 and FGFR2, presumably because of gene amplification (data not shown). Based on this data, further analysis may enable the identification of a specific subpopulation with gene amplification, and may contribute to the development of a novel molecular-targeted therapy for patients with gastric cancer (Fig.…”