Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 18, Pages 4784-4793Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1096
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Funding
- Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO)
- Ministry of Health, Labor, and Welfare
- Japan Society for the Promotion of Science (JSPS) [24790340]
- Third-Term Comprehensive Control Research for Cancer [H25-Young Scientists-009]
- Grants-in-Aid for Scientific Research [26640095, 24790340] Funding Source: KAKEN
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Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC). Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis. Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power. Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence. (C)2014 AACR.
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