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

Abstract

BackgroundAlthough 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.MethodsWe 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.ResultsSeveral 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.ConclusionsFormalin-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.

Future directions in the treatment of osteosarcoma

“…A locus at 14q32 associated with miR-382, miR-134 and miR-544 has demonstrated an inverse correlation between aggressive tumor behavior and residual expression of microRNAs. [9, 10] DNA methylation analysis may reveal patterns with prognostic significance. [11] Further evaluation and prospective validation of these markers in future studies will establish their role in prognostication of tumor response and survival outcomes.…”

MicroRNA-433 regulates apoptosis by targeting PDCD4 in human osteosarcoma cells

“…The present study demonstrated that miR-433 was upregulated in osteosarcoma tissues compared with the adjacent normal tissues, and inhibited osteosarcoma apoptosis. The present data, along with an analysis of a published dataset (27), showed that miR-433 was overexpressed in osteosarcoma tissues and cell lines. In combi nation with previous reports revealing the roles of miR-433 in various other types of cancer, including ovarian and gastric cancer (28,29), the present study further confirmed that miR-433 functions as an oncomiR in osteosarcoma.…”

Osteosarkoma pediatrikoarekiko suszeptibilitatean inplikatuta dauden aldaera genetikoak

“…Beste adibide bat 14q32 gune kromosomikoan dagoen miRNA-klusterra da, OSaren progresioarekin eta pronostikoarekin erlazionatu dena [52].…”