title: MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma.
abstract: Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53-CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance.
authors.affiliation: Department of Pathology, M D Anderson International Spain Madrid, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sánchez-Espiridión
authors.forename: Ana M
authors.initials: AM
authors.lastname: Martín-Moreno
authors.forename: Carlos
authors.initials: C
authors.lastname: Montalbán
authors.forename: Vianihuini
authors.initials: V
authors.lastname: Figueroa
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Alvés
authors.forename: Miguel
authors.initials: M
authors.lastname: Canales
authors.forename: Mónica
authors.initials: M
authors.lastname: Estévez
authors.forename: Javier
authors.initials: J
authors.lastname: Menarguez
authors.forename: Pilar
authors.initials: P
authors.lastname: Sabín
authors.forename: María C
authors.initials: MC
authors.lastname: Ruiz-Marcellán
authors.forename: Andrés
authors.initials: A
authors.lastname: Lopez
authors.forename: Pedro
authors.initials: P
authors.lastname: Sánchez-Godoy
authors.forename: Fernando
authors.initials: F
authors.lastname: Burgos
authors.forename: Carlos
authors.initials: C
authors.lastname: Santonja
authors.forename: José L
authors.initials: JL
authors.lastname: López
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.forename: Juan F
authors.initials: JF
authors.lastname: Garcia
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D020868:Gene Silencing; D006689:Hodgkin Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012334:RNA, Neoplasm / Q000235:genetics*; D016539:Reed-Sternberg Cells / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D004317:Doxorubicin
keywords: Hodgkin lymphoma; RT-polymerase chain reaction; clinical outcome; microRNA; molecular pathogenesis