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. 2014 Nov;49(11):1453-66.
doi: 10.1007/s00535-013-0904-0. Epub 2013 Nov 12.

A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma

Fatima Solange Pasini  1 , Bruno Zilberstein, Igor Snitcovsky, Rosimeire Aparecida Roela, Flavia R Rotea Mangone, Ulysses Ribeiro Jr, Suely Nonogaki, Glauber Costa Brito, Giovanna D Callegari, Ivan Cecconello, Venancio Avancini Ferreira Alves, José Eluf-Neto, Roger Chammas, Miriam Hatsue Honda Federico
Affiliations

A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma

Fatima Solange Pasini et al. J Gastroenterol. 2014 Nov.

Abstract

Background: The TNM Classification of Malignant Tumours (TNM) staging system is the primary means of determining a prognosis for gastric adenocarcinoma (GC). However, tumor behavior in the individual patient is unpredictable and in spite of treatment advances, a classification of 'advanced stage' still portends a poor prognosis. Thus, further insights from molecular analyses are needed for better prognostic stratification and determination of new therapeutic targets.

Methods: A total of fifty-one fresh frozen tumor samples from patients with histopathologically confirmed diagnoses of GC, submitted to surgery with curative intent, were included in the study. Total RNA was extracted from an initial group of fifteen samples matched for known prognostic factors, categorized into two subgroups, according to patient overall survival: poor (<24 months) or favorable (at or above 24 months), and hybridized to Affymetrix Genechip human genome U133 plus 2.0 for genes associated with prognosis selection. Thirteen genes were selected for qPCR validation using those initial fifteen samples plus additional thirty-six samples.

Results: A total of 108 genes were associated with poor prognosis, independent of tumor staging. Using systems biology, we suggest that this panel reflects the dampening of immune/inflammatory response in the tumor microenvironment level and a shift to Th2/M2 activity. A gene trio (OLR1, CXCL11 and ADAMDEC1) was identified as an independent marker of prognosis, being the last two markers validated in an independent patient cohort.

Conclusions: We determined a panel of three genes with prognostic value in gastric cancer, which should be further investigated. A gene expression profile suggestive of a dysfunctional inflammatory response was associated with unfavorable prognosis.

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Figures

Fig. 1
Fig. 1
Dendrogram representing the unsupervised hierarchical clustering using Euclidean distance and average linkage as parameters. The genes are arranged in each row, and the samples are in columns. Five samples from patients with good prognosis (C2–C6) were correctly classified, while two samples, C8 and C9, were misclassified, together with samples from patients with a poor prognosis (T2–T9)
Fig. 2
Fig. 2
Graphical representation of the most important biological functions associated with 108 differentially expressed genes identified when comparing tumor samples from gastric adenocarcinoma patients with poor or favorable prognosis
Fig. 3
Fig. 3
Distribution of correlations and relevance networks calculated using data from favorable or poor prognosis patients. a, b The correlations between 108 differentially expressed genes (DEGs) (red curve) were compared to a reference dataset generated from random sampling (blue curve). c, d Relevance networks constructed using co-expressed DEGs (Pearson correlation, P < 0.05) annotated as involved in global immune response. The favorable prognosis network showed more positive correlations than the poor prognosis network
Fig. 4
Fig. 4
Kaplan–Meier curves for overall survival according to tumor expression of mRNA CLND10 (a), and DAZ1–4 (b). The patients were classified as positive (up) or negative (equal to or below) in accordance with the cutoff optimized by the ROC curve. Patients with positive tumor expression for these markers tended to have worse overall survival (Log-rank test). Kaplan–Meier curves for overall survival according to tumor expression of the score predictive of survival (c). Patients were classified as having high-risk (−0.23 to −2.09) and low-risk (−33.26 to −2.10) scores according to the joint mRNA expression of CXCL11 and OLR1 in the primary tumor. Patients with high-risk predictive scores had worse overall survival (P = 0.003). n number of patients
Fig. 5
Fig. 5
Immunostaining of CXC11 in gastric adenocarcinoma. a CXCL11 faintly expressed in the cytoplasm of epithelial cells of intestinal-type tubular gastric adenocarcinoma; b Moderate expression in the cytoplasm of epithelial cells of tubule-papillary gastric adenocarcinoma; c Intratumoral inflammatory response: strong macrophage reactivity for CXCL11 (3+/4+). Some plasma cells are faintly positive (1+/4+), whereas lymphocytes are virtually negative; d Intratumoral lymphoid aggregate depicting pale reactivity for CXCL11. a–c ×400 and d ×200
Fig. 6
Fig. 6
Immunostaining of OLR1 in gastric adenocarcinoma. a Both tumor and non-neoplastic epithelial cells were negative for OLR1; b Moderate focal positivity for OLR1 in epithelial neoplastic cells; c Positive reaction in intratumoral macrophages, plasma cells and fibroblasts; d Intratumoral fibroblastic reaction displaying moderate reactivity for OLR1, in contrast with epithelial tumor cells which do not express OLR1 in this sample. a ×200 and b–d ×400
Fig. 7
Fig. 7
A schematic diagram of gene expression and immune cells that could be associated with poor prognosis of patients with gastric adenocarcinoma (Adapted from Laskin [38]). Genes induced are shown by arrows pointing up and those that were downregulated are indicated by arrows pointing down. Expression data determined by microarray and validated by qPCR assays are indicated by filled arrows and those determined only by microarray assay are indicated by open arrow. Other genes indicated were extracted from literature review. Our data suggest a diminished Th1/M1 polarization and a shift to Th2/M2 activity, associated with an unfavorable prognosis of gastric cancer
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