A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma.
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.
Departamento de Radiologia e Oncologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Fatima Solange
FS
Pasini
Bruno
B
Zilberstein
Igor
I
Snitcovsky
Rosimeire Aparecida
RA
Roela
Flavia R Rotea
FR
Mangone
Ulysses
U
Ribeiro
Suely
S
Nonogaki
Glauber Costa
GC
Brito
Giovanna D
GD
Callegari
Ivan
I
Cecconello
Venancio Avancini Ferreira
VA
Alves
José
J
Eluf-Neto
Roger
R
Chammas
Miriam Hatsue Honda
MH
Federico
D051722:ADAM Proteins / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000276:immunology; D054371:Chemokine CXCL11 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D059467:Transcriptome / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology
D014408:Biomarkers, Tumor; C515202:CXCL11 protein, human; D054371:Chemokine CXCL11; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D051722:ADAM Proteins; C108169:decysin