%0 Journal Article
%T MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32
%A Andrew D Kelly
%A Benjamin Haibe-Kains
%A Katherine A Janeway
%A Katherine E Hill
%A Eleanor Howe
%A Jeffrey Goldsmith
%A Kyle Kurek
%A Antonio R Perez-Atayde
%A Nancy Francoeur
%A Jian-Bing Fan
%A Craig April
%A Hal Schneider
%A Mark C Gebhardt
%A Aedin Culhane
%A John Quackenbush
%A Dimitrios Spentzos
%J Genome Medicine
%D 2013
%I BioMed Central
%R 10.1186/gm406
%X We performed miRNA and mRNA microarray FFPE 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.Several miRNA-based models with as few as 5 miRNAs were prognostic independently of pathologically assessed chemoresponse (median RFS: 59 months vs. not-yet-reached; adjusted HR=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 RFS: 59 vs. not-yet-reached; HR=3.91; p=0.002). Most prognostic miRNAs are 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 (75-80% accuracy), which did not overlap with prognostic profiles.FFPE tissue-derived miRNA patterns are a powerful prognostic tool for risk-stratified osteosarcoma management strategies. Combined miRNA/mRNA analysis supports a possible role of the 14q32 locus in osteosarcoma progression and outcome. Our study creates a paradigm for FFPE-based miRNA biomarker studies in cancer.
%U http://genomemedicine.com/content/5/1/2/abstract