Multiple myeloma is the second most common hematological malignancy characterized by focal lesions of malignant plasma cells in the bone marrow. These lesions contain subclones that directly influence survival of patients. Bone marrow biopsies are single-site biopsies and thus cannot contain all information about the tumor. In contrast, liquid biopsies analyze circulating cells and molecules that are secreted from all sites of the tumor. Long noncoding RNA molecules are one class of these molecules. We performed a two-phase biomarker study investigating lncRNA expression profiles in exosomes of peripheral blood serum of newly diagnosed multiple myeloma (MM) patients, monoclonal gammopathy of undetermined significance (MGUS) patients in comparison with healthy donors (HD). Surprisingly, this analysis revealed dysregulation of only one exosomal lncRNA PRINS in MM vs HD. Overall, MM and MGUS patients were distinguished from HD with sensitivity of 84.9% and specificity of 83.3%. Our study suggests a possible diagnostic role for exosomal lncRNA PRINS in monoclonal gammopathies patients.

• Klíčová slova
• biomarker, long noncoding RNA, monoclonal gammopathy of undetermined significance, multiple myeloma, qPCR,
• MeSH
• dospělí MeSH
• exozómy metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mnohočetný myelom * krev   diagnóza   mortalita   MeSH
• přežití bez známek nemoci MeSH
• RNA dlouhá nekódující krev   MeSH
• RNA nádorová krev   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• Názvy látek
• RNA dlouhá nekódující MeSH
• RNA nádorová MeSH

BACKGROUND: The genome of multiple myeloma (MM) cells is extremely unstable, characterized by a complex combination of structure and numerical abnormalities. It seems that there are several "myeloma subgroups" which differ in expression profile, clinical manifestations, prognoses and treatment response. In our previous work, the list of 35 candidate genes with a known role in carcinogenesis and associated with centrosome structure/function was used as a display of molecular heterogeneity with an impact in myeloma pathogenesis. The current study was devoted to establish a risk stratification model based on the aforementioned candidate genes. METHODS: A total of 151 patients were included in this study. CD138+ cells were separated by magnetic-activated cell sorting (MACS). Gene expression profiling (GEP) and Interphase FISH with cytoplasmic immunoglobulin light chain staining (cIg FISH) were performed on plasma cells (PCs). All statistical analyses were performed using freeware R and its additional packages. Training and validation cohort includes 73 and 78 patients, respectively. RESULTS: We have finally established a model that includes 12 selected genes (centrosome associated gene pattern, CAGP) which appears to be an independent prognostic factor for MM stratification. We have shown that the new CAGP model can sub-stratify prognosis in patients without TP53 loss as well as in IMWG high risk patients' group. CONCLUSIONS: We assume that newly established risk stratification model complements the current prognostic panel used in multiple myeloma and refines the classification of patients in relation to the disease risks. This approach can be used independently as well as in combination with other factors.

• Klíčová slova
• Gene expression profiling, Multiple myeloma, Risk stratification,
• MeSH
• centrozom metabolismus   MeSH
• dospělí MeSH
• hodnocení rizik * MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• přežití bez známek nemoci MeSH
• regulace genové exprese u nádorů * MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH

Poor outcome of extramedullary disease in multiple myeloma patients and lack of outcome predictors prompt continued search for new markers of the disease. In this report, we show circulating microRNA distinguishing multiple myeloma patients with extramedullary disease from myeloma patients without such manifestation and from healthy donors. MicroRNA-130a was identified by TaqMan Low Density Arrays and verified by quantitative PCR on 144 serum samples (59 multiple myeloma, 55 myeloma with extramedullary disease, 30 healthy donors) in test and validation cohorts as being down-regulated in myeloma patients with extramedullary disease. Circulating microRNA-130a distinguished myeloma patients with extramedullary disease from healthy donors with specificity of 90.0% and sensitivity of 77.1%, patients with extramedullary disease from newly diagnosed multiple myeloma patients with specificity of 77.1% and sensitivity of 34.3% in the test cohort and with specificity of 91.7% and sensitivity of 30.0% in the validation cohort of patients. Circulating microRNA-130a in patients with extramedullary myeloma was associated with bone marrow plasma cells infiltration. Further, microRNA-130a was decreased in bone marrow plasma cells obtained from patients with extramedullary myeloma in comparison to bone marrow plasma cells of myeloma patients without such manifestation, but it was increased in tumor site plasma cells of patients with extramedullary disease compared to bone marrow plasma cells of such patients (p<0.0001). Together, our data suggest connection between lower level of microRNA-130a and extramedullary disease and prompt further work to evaluate this miRNA as a marker of extramedullary disease in multiple myeloma.

• MeSH
• dospělí MeSH
• kostní dřeň patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA analýza   krev   genetika   MeSH
• mnohočetný myelom krev   diagnóza   genetika   patologie   MeSH
• nádorové biomarkery analýza   krev   genetika   MeSH
• plazmatické buňky patologie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mikro RNA MeSH
• MIRN130 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH

Characteristic recurrent copy number aberrations (CNAs) play a key role in multiple myeloma (MM) pathogenesis and have important prognostic significance for MM patients. Array-based comparative genomic hybridization (aCGH) provides a powerful tool for genome-wide classification of CNAs and thus should be implemented into MM routine diagnostics. We demonstrate the possibility of effective utilization of oligonucleotide-based aCGH in 91 MM patients. Chromosomal aberrations associated with effect on the prognosis of MM were initially evaluated by I-FISH and were found in 93.4% (85/91). Incidence of hyperdiploidy was 49.5% (45/91); del(13)(q14) was detected in 57.1% (52/91); gain(1)(q21) occurred in 58.2% (53/91); del(17)(p13) was observed in 15.4% (14/91); and t(4;14)(p16;q32) was found in 18.6% (16/86). Genome-wide screening using Agilent 44K aCGH microarrays revealed copy number alterations in 100% (91/91). Most common deletions were found at 13q (58.9%), 1p (39.6%), and 8p (31.1%), whereas gain of whole 1q was the most often duplicated region (50.6%). Furthermore, frequent homozygous deletions of genes playing important role in myeloma biology such as TRAF3, BIRC1/BIRC2, RB1, or CDKN2C were observed. Taken together, we demonstrated the utilization of aCGH technique in clinical diagnostics as powerful tool for identification of unbalanced genomic abnormalities with prognostic significance for MM patients.

• MeSH
• celogenomová asociační studie * MeSH
• chromozomální aberace * MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom diagnóza   genetika   MeSH
• nádorové proteiny genetika   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srovnávací genomová hybridizace metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• nádorové proteiny MeSH

BACKGROUND: Multiple myeloma (MM) is a low proliferative tumor of postgerminal center plasma cell (PC). Centrosome amplification (CA) is supposed to be one of the mechanisms leading to chromosomal instability. Also, CA is associated with deregulation of cell cycle, mitosis, DNA repair and proliferation. The aim of our study was to evaluate the prognostic significance and possible role of CA in pathogenesis and analysis of mitotic genes as mitotic disruption markers. DESIGN AND METHODS: A total of 173 patients were evaluated for this study. CD138+ cells were separated by MACS. Immunofluorescent labeling of centrin was used for evaluation of centrosome amplification in PCs. Interphase FISH with cytoplasmic immunoglobulin light chain staining (cIg FISH) and qRT-PCR were performed on PCs. RESULTS: Based on the immunofluorescent staining results, all patients were divided into two groups: CA positive (38.2%) and CA negative (61.8%). Among the newly diagnosed patients, worse overall survival was indicated in the CA negative group (44/74) in comparison to the CA positive group (30/74) (P = 0.019). Gene expression was significantly down-regulated in the CA positive group in comparison to CA negative in the following genes: AURKB, PLK4, TUBG1 (P < 0.05). Gene expression was significantly down-regulated in newly diagnosed in comparison to relapsed patients in the following genes: AURKA, AURKB, CCNB1, CCNB2, CETN2, HMMR, PLK4, PCNT, and TACC3 (P < 0.05). CONCLUSIONS: Our findings indicate better prognosis for CA positive newly diagnosed patients. Considering revealed clinical and gene expression heterogeneity between CA negative and CA positive patients, there is a possibility to characterize centrosome amplification as a notable event in multiple myeloma pathogenesis.

• MeSH
• centrozom ultrastruktura   MeSH
• dospělí MeSH
• hybridizace in situ fluorescenční MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitóza MeSH
• mnohočetný myelom farmakoterapie   genetika   MeSH
• oprava DNA MeSH
• polymerázová řetězová reakce MeSH
• prognóza MeSH
• proliferace buněk MeSH
• recidiva MeSH
• regulace genové exprese u nádorů * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• separace buněk MeSH
• stanovení celkové genové exprese MeSH
• syndekan-1 metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• syndekan-1 MeSH