title: Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients.
abstract: Despite improved therapeutic regimens, primary CNS lymphoma (PCNSL) remains a therapeutic challenge. A prognostic classification of PCNSL patients may represent an important step towards optimised patient-adapted therapy. However, only higher age and low Karnofsky Performance Status (KPS) have repeatedly been reported to be associated with shorter overall survival (OS). Here we characterised microRNA (miRNA) fingerprints in the blood of PCNSL patients with short-term survival (STS) versus long-term survival (LTS) to assess their potential as novel prognostic biomarkers. Blood was collected from patients enrolled in the G-PCNSL-SG1 trial, a phase III study for patients with newly diagnosed PCNSL. miRNAs were extracted from the blood and analysed by next generation sequencing. The STS group comprised 20 patients with a median OS of 3 months and was compared to 20 LTS patients with a median OS of 55 months. The cohorts were balanced for age and KPS. Twelve annotated miRNAs were significantly deregulated between the two groups. Among them, miR-151a-5p and miR-151b exhibited the most prominent differences. Importantly, the combination of several miRNA allowed for a good separation between short- and long-term survivors with maximal Area Under Curve (AUC) above 0.75. Besides the known miRNAs we identified putative novel miRNA candidates with potential regulatory influence of PCNSL. Finally, the differential regulation of the most promising candidate miRNAs was confirmed by real-time polymerase chain reaction (PCR) in a validation cohort consisting of 20 STS and LTS patients. In conclusion, peripheral blood miRNA expression patterns hold promise as a prognostic tool in PCNSL patients.
authors.affiliation: Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: patrick.roth@usz.ch.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center, 69121 Heidelberg, Germany.
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
authors.affiliation: Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Paula
authors.initials: P
authors.lastname: Codo
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center, 69121 Heidelberg, Germany.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Bauer
authors.affiliation: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Leidinger
authors.affiliation: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Meese
authors.affiliation: Department of Hematology and Oncology, Charité, 12200 Berlin, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.affiliation: Department of Hematology and Oncology, Charité, 12200 Berlin, Germany.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Korfel
authors.affiliation: Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D016543:Central Nervous System Neoplasms / Q000097:blood / Q000235:genetics / Q000401:mortality*; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000097:blood / Q000235:genetics / Q000401:mortality*; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D017741:Survivors
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: Biomarker; Next generation sequencing; Primary CNS lymphoma; Prognostic factor; microRNA