TY - JOUR
T1 - MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma
AU - Sánchez-Espiridión, Beatriz
AU - Martín-Moreno, Ana M.
AU - Montalbán, Carlos
AU - Figueroa, Vianihuini
AU - Vega, Francisco
AU - Younes, Anas
AU - Medeiros, L. Jeffrey
AU - Alvés, Francisco J.
AU - Canales, Miguel
AU - Estévez, Mónica
AU - Menarguez, Javier
AU - Sabín, Pilar
AU - Ruiz-Marcellán, María C.
AU - Lopez, Andrés
AU - Sánchez-Godoy, Pedro
AU - Burgos, Fernando
AU - Santonja, Carlos
AU - López, José L.
AU - Piris, Miguel A.
AU - Garcia, Juan F.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Clinical outcome
KW - Hodgkin lymphoma
KW - MicroRNA
KW - Molecular pathogenesis
KW - RT-polymerase chain reaction
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U2 - 10.1111/bjh.12390
DO - 10.1111/bjh.12390
M3 - Article
C2 - 23725219
AN - SCOPUS:84880270342
SN - 0007-1048
VL - 162
SP - 336
EP - 347
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -