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.
Subject(s)
Biomarkers, Tumor/genetics , Hodgkin Disease/genetics , MicroRNAs/genetics , RNA, Neoplasm/genetics , Adult , Aged , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Doxorubicin/pharmacology , Female , Gene Expression Profiling/methods , Gene Silencing , Hodgkin Disease/drug therapy , Hodgkin Disease/pathology , Humans , Male , MicroRNAs/metabolism , Middle Aged , Neoplasm Staging , Oligonucleotide Array Sequence Analysis/methods , Reed-Sternberg Cells/metabolism , Survival Analysis , Treatment Outcome , Tumor Cells, Cultured , Tumor Microenvironment , Young AdultABSTRACT
AIMS: Clear cell papillary cystadenoma (CCPC) is associated with von Hippel-Lindau disease (VHLD), but rarely involves mesosalpinx and broad ligament (M/BL). This study provides new data about its behaviour and immunophenotype. METHODS AND RESULTS: We performed an analysis of four benign cases of CCPC of M/BL with either characteristic clinical features or genetic markers [loss of heterozygosity (LOH)] of VHLD in patients ranging from 24 to 36 years and a sporadic case in a 52-year-old presenting with peritoneal metastases. All CCPCs were papillary but had solid and tubular areas. Haemorrhage, thrombosis and scarring were constant features and related to an unusual pattern of sub-epithelial vascularity. All clear or oxyphilic cells co-expressed cytokeratin 7 (CK7), CAM5.2 and vimentin, with strong apical CD10 and nuclear paired box gene 2 (PAX2) immunoreactivity. Three cases also showed positivity for VHL40, epithelial membrane antigen (EMA), Wilms' tumour suppressor gene (WT-1) and cancer antigen 125 (CA125) but only one expressed renal cell carcinoma (RCC) antigen. Vascular plexus overexpressed nuclear and cytoplasmic WT-1. CONCLUSION: The VHLD-associated cases appeared to be benign, but the sporadic case exhibited a low malignant potential. CCPCs show histological and immunophenotypical similarities with the recently reported clear cell papillary RCC, although the previously unreported apical CD10 and nuclear PAX2 expression may be related to their mesonephric origin. CCPC has a distinctive sub-epithelial vascular pattern that is consistent with its pathogenesis.
Subject(s)
Broad Ligament/pathology , Cystadenoma, Papillary/pathology , Fallopian Tube Neoplasms/pathology , Fallopian Tubes/pathology , Uterine Neoplasms/pathology , von Hippel-Lindau Disease/pathology , Adult , Biomarkers, Tumor/metabolism , Broad Ligament/metabolism , Cystadenoma, Papillary/complications , Cystadenoma, Papillary/genetics , Cystadenoma, Papillary/metabolism , Fallopian Tube Neoplasms/complications , Fallopian Tube Neoplasms/genetics , Fallopian Tube Neoplasms/metabolism , Fallopian Tubes/metabolism , Female , Humans , Loss of Heterozygosity , Middle Aged , Neoplasms, Multiple Primary , Uterine Neoplasms/genetics , Uterine Neoplasms/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Young Adult , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/genetics , von Hippel-Lindau Disease/metabolismABSTRACT
Follicular lymphomas (FLs) usually carry BCL2 translocations although BCL6 translocations are also present. We explored relationships between translocations status and clinical or histological parameters at diagnosis in 182 patients stratified in four groups: BCL2-/BCL6-, BCL2+/BCL6-, BCL2-/BCL6+ and BCL2+/BCL6+. BCL2-/BCL6- and BCL2+/BCL6-. Double negative cases were ascribed to lower histological grades. In contrast, BCL2-/BCL6+ cases corresponded to higher grades. However, a majority of BCL2+/BCL6+ tumours were classified as lower grades. These results were reinforced by the finding that double positive patients had lower LDH levels and PS than those with solitary BCL6 rearrangements. Bone marrow involvement was more frequent in BCL2+/BCL6+ compared with BCL2-/BCL6+ tumours. Our data confirm the presence of a relationship between histological grade and translocation status, suggesting that FLs carrying BCL6 translocations probably constitute a special biological subtype. Clinical and histological differences between BCL2-/BCL6+ and BCL2+/BCL6+ tumours could reflect an interplay between both translocations.
