MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival - PubMed (original) (raw)

Multicenter Study

. 2009 Oct 1;15(19):6192-200.

doi: 10.1158/1078-0432.CCR-09-1467. Epub 2009 Sep 29.

Giang Huong Nguyen, Elise D Bowman, Yiqiang Zhao, Anuradha Budhu, Aaron J Schetter, Rosemary Braun, Mark Reimers, Kensuke Kumamoto, Duncan Hughes, Nasser K Altorki, Alan G Casson, Chang-Gong Liu, Xin Wei Wang, Nozomu Yanaihara, Nobutoshi Hagiwara, Andrew J Dannenberg, Masao Miyashita, Carlo M Croce, Curtis C Harris

Affiliations

Multicenter Study

MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival

Ewy A Mathé et al. Clin Cancer Res. 2009.

Abstract

Purpose: The dismal outcome of esophageal cancer patients highlights the need for novel prognostic biomarkers, such as microRNAs (miRNA). Although recent studies have established the role of miRNAs in esophageal carcinoma, a comprehensive multicenter study investigating different histologic types, including squamous cell carcinoma (SCC) and adenocarcinoma with or without Barrett's, is still lacking.

Experimental design: miRNA expression was measured in cancerous and adjacent noncancerous tissue pairs collected from 100 adenocarcinoma and 70 SCC patients enrolled at four clinical centers from the United States, Canada, and Japan. Microarray-based expression was measured in a subset of samples in two cohorts and was validated in all available samples.

Results: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. When comparing cancerous tissue expression between adenocarcinoma and SCC patients, miR-194 and miR-375 were elevated in adenocarcinoma patients. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. Associations with prognosis were independent of tumor stage or nodal status, cohort type, and chemoradiation therapy.

Conclusions: Our multicenter-based results highlight miRNAs involved in major histologic types of esophageal carcinoma and uncover significant associations with prognosis. Elucidating miRNAs relevant to esophageal carcinogenesis is potentially clinically useful for developing prognostic biomarkers and identifying novel drug targets and therapies.

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Figures

Figure 1

Figure 1

Study design flow chart. Differential expression analysis and associations with prognosis were performed in patients with ADC and SCC, separately. Microarray analysis was performed on a subset of samples as a hypothesis-generating tool to subsequently focus further validation on a subset of miRNAs that are potentially relevant to esophageal carcinogenesis. Validation using qRT-PCR was performed on all samples available.

Figure 2

Figure 2

qRT-PCR validation of differentially expressed miRNAs. A) Altered expression between cancerous tissue (NCT) and non-cancerous tissue (NCT) in ADC patients is shown. Mir-21, mir-223, mir-192, and mir-194 are over-expressed in tumors while mir-203 is under-expressed in tumors. B) Differential expression between CT and NCT in SCC patients demonstrates that mir-21 is up-regulated and mir-375 is down-regulated in SCC tumors. All expression values are normalized to RNAU66, and differential expression is statistically significant (P<0.005).

Figure 3

Figure 3

Kaplan-Meier Analysis depicting associations with qRT-PCR miRNA expression and survival. MiRNA expression values were dichotomized into low and high groups, using the within cohort median expression value as a cutoff. A) Associations observed in adenocarcinoma (ADC) patients with and without Barrett's. Reduced expression of mir-375 in cancerous tissue of ADC patients with Barrett's is associated with worse prognosis. This association is not observed in ADC patients without Barrett's. Survival profiles were compared using the log rank test. B) Associations observed in squamous cell carcinoma (SCC) patients. Elevated expression of mir-21 in non-cancerous tissue is associated with worse prognosis. This association is not found when cancerous tissue expression is evaluated.

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