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MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32

Andrew D Kelly1, Benjamin Haibe-Kains23, Katherine A Janeway4, Katherine E Hill1, Eleanor Howe2, Jeffrey Goldsmith5, Kyle Kurek6, Antonio R Perez-Atayde6, Nancy Francoeur1, Jian-Bing Fan7, Craig April7, Hal Schneider8, Mark C Gebhardt9, Aedin Culhane2, John Quackenbush2 and Dimitrios Spentzos1*

Author Affiliations

1 Division of Hematology/Oncology, Sarcoma Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA

2 Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA

3 Bioinformatics and Computational Genomics, Institut de Recherches Cliniques de Montréal, 110 Avenue Des Pins O, Montreal, Quebec H2W 1R7, Canada

4 Division of Hematology/Oncology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02215, USA

5 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA

6 Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02215, USA

7 Illumina Inc., 5200 Illumina Way, San Diego, CA 92122, USA

8 Molecular Genetics Core Facility, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02215, USA

9 Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA

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Genome Medicine 2013, 5:2  doi:10.1186/gm406

Published: 22 January 2013

Abstract

Background

Although microRNAs (miRNAs) are implicated in osteosarcoma biology and chemoresponse, miRNA prognostic models are still needed, particularly because prognosis is imperfectly correlated with chemoresponse. Formalin-fixed, paraffin-embedded tissue is a necessary resource for biomarker studies in this malignancy with limited frozen tissue availability.

Methods

We performed miRNA and mRNA microarray formalin-fixed, paraffin-embedded assays in 65 osteosarcoma biopsy and 26 paired post-chemotherapy resection specimens and used the only publicly available miRNA dataset, generated independently by another group, to externally validate our strongest findings (n = 29). We used supervised principal components analysis and logistic regression for survival and chemoresponse, and miRNA activity and target gene set analysis to study miRNA regulatory activity.

Results

Several miRNA-based models with as few as five miRNAs were prognostic independently of pathologically assessed chemoresponse (median recurrence-free survival: 59 months versus not-yet-reached; adjusted hazards ratio = 2.90; P = 0.036). The independent dataset supported the reproducibility of recurrence and survival findings. The prognostic value of the profile was independent of confounding by known prognostic variables, including chemoresponse, tumor location and metastasis at diagnosis. Model performance improved when chemoresponse was added as a covariate (median recurrence-free survival: 59 months versus not-yet-reached; hazard ratio = 3.91; P = 0.002). Most prognostic miRNAs were located at 14q32 - a locus already linked to osteosarcoma - and their gene targets display deregulation patterns associated with outcome. We also identified miRNA profiles predictive of chemoresponse (75% to 80% accuracy), which did not overlap with prognostic profiles.

Conclusions

Formalin-fixed, paraffin-embedded tissue-derived miRNA patterns are a powerful prognostic tool for risk-stratified osteosarcoma management strategies. Combined miRNA and mRNA analysis supports a possible role of the 14q32 locus in osteosarcoma progression and outcome. Our study creates a paradigm for formalin-fixed, paraffin-embedded-based miRNA biomarker studies in cancer.