Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer.
BACKGROUND
MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR-375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC).


METHODS
Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports.


RESULTS
In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41-8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC.


CONCLUSIONS
In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology.
a Department of Experimental Clinical Oncology , Aarhus University Hospital , Aarhus , Denmark.
Mette
M
Winther
a Department of Experimental Clinical Oncology , Aarhus University Hospital , Aarhus , Denmark.
Jan
J
Alsner
b Department of Pathology , Aarhus University Hospital , Aarhus , Denmark.
Trine
T
Tramm
c Department of Oncology , Rigshospitalet , Copenhagen , Denmark.
Lene
L
Baeksgaard
d Department of Oncology , Odense University Hospital , Odense , Denmark.
Eva
E
Holtved
e Department of Oncology , Aarhus University Hospital , Aarhus , Denmark.
Marianne
M
Nordsmark
D000230:Adenocarcinoma / Q000235:genetics* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D059186:Chemoradiotherapy, Adjuvant; D004938:Esophageal Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016629:Esophagectomy; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D011859:Radiography; D012189:Retrospective Studies; D015996:Survival Rate
D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs