title: Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas.
abstract: A common and aggressive subtype of soft-tissue sarcoma, undifferentiated pleomorphic sarcoma (UPS) was examined to determine the role of micro-RNAs (miRNAs) in modulating distant metastasis. Following histopathologic review, 110 fresh frozen clinically annotated UPS samples were divided into two independent cohorts for Training (42 patients), and Validation (68 patients) analyses. Global miRNA profiling on the Training Set and functional analysis in vitro suggested that miRNA-138 and its downstream RHO-ROCK cell adhesion pathway was a convergent target of miRNAs associated with the development of metastasis. A six-miRNA signature set prognostic of distant metastasis-free survival (DMFS) was developed from Training Set miRNA expression values. Using the six-miRNA signature, patients were successfully categorized into high- and low-risk groups for DMFS in an independent Validation Set, with a hazard ratio (HR) of 2.25 (p = 0.048). After adjusting for other known prognostic variables such as age, gender, tumor grade, size, depth, and treatment with radiotherapy, the six-miRNA signature retained prognostic value with a HR of 3.46 (p < 0.001). A prognostic miRNA biomarker for clinical validation was thus identified along with a functional pathway that modulates UPS metastatic phenotype.
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.|Département of Radiation Oncology, Centre Hospitalier de L'Université de Montréal, Montréal, QC, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Hui
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.affiliation: Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Nalan
authors.initials: N
authors.lastname: Gokgoz
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Bruce
authors.affiliation: Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Williams
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Catton
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gladdy
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Department of Pathology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Dickson
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.|Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D054460:rho-Associated Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D054460:rho-Associated Kinases
keywords: biomarker; metastasis; microRNA; prognostic; sarcoma