title: Efficient identification of miRNAs for classification of tumor origin.
abstract: Carcinomas of unknown primary origin constitute 3% to 5% of all newly diagnosed metastatic cancers, with the primary source difficult to classify with current histological methods. Effective cancer treatment depends on early and accurate identification of the tumor; patients with metastases of unknown origin have poor prognosis and short survival. Because miRNA expression is highly tissue specific, the miRNA profile of a metastasis may be used to identify its origin. We therefore evaluated the potential of miRNA profiling to identify the primary tumor of known metastases. Two hundred eight formalin-fixed, paraffin-embedded samples, representing 15 different histologies, were profiled on a locked nucleic acid-enhanced microarray platform, which allows for highly sensitive and specific detection of miRNA. On the basis of these data, we developed and cross-validated a novel classification algorithm, least absolute shrinkage and selection operator, which had an overall accuracy of 85% (CI, 79%-89%). When the classifier was applied on an independent test set of 48 metastases, the primary site was correctly identified in 42 cases (88% accuracy; CI, 75%-94%). Our findings suggest that miRNA expression profiling on paraffin tissue can efficiently predict the primary origin of a tumor and may provide pathologists with a molecular diagnostic tool that can improve their capability to correctly identify the origin of hitherto unidentifiable metastatic tumors and, eventually, enable tailored therapy.
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Rolf
authors.initials: R
authors.lastname: Søkilde
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Department of Oncology, State University Hospital, Copenhagen, Denmark.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Møller
authors.affiliation: Department of Pathology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Alastair
authors.initials: A
authors.lastname: Hansen
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Poul E
authors.initials: PE
authors.lastname: Høiby
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Thorarinn
authors.initials: T
authors.lastname: Blondal
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Boye S
authors.initials: BS
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, State University Hospital, Copenhagen, Denmark.
authors.forename: Gedske
authors.initials: G
authors.lastname: Daugaard
authors.affiliation: Exiqon A/S, Vedbæk, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Møller
authors.affiliation: Exiqon A/S, Vedbæk, Denmark. Electronic address: tlitman@hotmail.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Litman
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009382:Neoplasms, Unknown Primary / Q000145:classification* / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009928:Organ Specificity / Q000235:genetics; D016612:Paraffin Embedding; D017423:Sequence Analysis, RNA / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs