Gain of 1q21 Is an Unfavorable Genetic Prognostic Factor for Multiple Myeloma Patients Treated with High-Dose Chemotherapy

Němec, Pavel; Zemanová, Zuzana; Grešlíková, Henrieta; Michalova, Kyra; Filková, Hana; Tajtlová, Jana; Kralova, Dana; Kupská, Renata; Smetana, Jan; Krejčí, Marta; Pour, Luděk; Zahradová, Lenka; Sandecká, Viera; Adam, Zdeněk; Büchler, Tomáš; Špıčka, Ivan; Gregora, Evžen; Kuglík, Petr; Hájek, Roman

doi:10.1016/j.bbmt.2009.11.025

Cited by 64 publications

(50 citation statements)

References 32 publications

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“…In our hands the presence of gain 1q21 did not correlate with the occurrence of any other of the studied chromosomal abnormalities in contrast to findings of Chen and collaborators who detected an association with del(13)(q14) [17]. Our next study carried out on more patients showed that gain1q21 is associated with significantly shorter OS intervals (p=0.001) [28]. Our results suggest that gain 1q21 is negative prognostic factor in MM patients.…”

Section: Discussioncontrasting

confidence: 55%

Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation

Grešlíková

Zaoralová²,

Filková³

et al. 2010

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Multiple myeloma (MM) is the second most common haematological malignancy. It is characterized by malignant transformation and clonal proliferation of B-lymphocytes with the accumulation of malignant plasma cells in the bone marrow. The incidence of MM increases with age. The average age at presentation is 62 years in men and 61 years in women [1]. Patients below 40 years of age represent less than 3% of all cases. For many years, conventional chemotherapy with combination of melphalan and prednisone was the standard treatment, resulting in overall survival (OS) of approximately 3 years [2]. Currently, high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation is recommended for patients below the age of 65 [3,4]. This treatment extends the OS to 4-5 years [5], with approximately 28% of patients surviving 5 or more years [6]. Despite this relative treatment success, MM remains an incurable disease. Many prognostic factors for MM have been identified. The presence of numerical and/or structural chromosomal aberrations is one of the most important indicators for the prognostic assessments.Due to low proliferation activity of MM cells, conventional cytogenetics detects chromosomal changes in as few as 26-40% of cases [7,8]. In contrast, the technique of interphase fluorescent in situ hybridization (I-FISH) in combination with cytoplasm immunoglobulin staining or immunomagnetic separation of plasma cells enables detection of specific abnormalities in up to 86-98% of patients [9,10,11] Received April 8, 2009Malignant plasma cells in multiple myeloma (MM) are frequently characterized by complex karyotypes and chromosome instability. These cytogenetic changes are considered important prognostic indicators in MM patients. We have studied samples from 68 patients with newly diagnosed MM who were treated with high-dose chemotherapy and autologous stem cell transplantation. G-banding revealed abnormal karyotypes in 14 of 55 patients (25%) who had informative conventional cytogenetics. The combination of cytoplasmic immunoglobulin light chain labeling and interphase fluorescent in situ hybridization (cIg-FISH) revealed the presence of genetic aberrations in 53 of 68 patients (78%). Chromosome 13 abnormalities were found in 33 patients (50%) and IgH rearrangements in 36 patients (56.25%). In IgH positive patients we performed subsequent examinations of IgH affecting translocations t(4;14) and t(11;14) and we found translocation t(11;14) in 8 patients (12.5%) and t(4;14) in 10 patients (15.5%). The occurrences of others chromosomal abnormalities with known prognostic impact in MM were as follows: del(17)(p13) was present in 5 patients (9.8%) and gain 1q21 in 14 patients (36%). Analysis of survival of patients with different cytogenetic abnormalities revealed shorter overall survival (OS) in patients with IgH rearrangements (p=0.020) and trend to shorter OS in patients with gain 1q21 (p=0.064), respectively. Remarkably, patients with two or more aberrations had significantly shorter overall surviva...

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Section: Discussioncontrasting

confidence: 55%

Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation

Grešlíková

Zaoralová²,

Filková³

et al. 2010

neo

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“…Interestingly, the miR-744 'low' expression group of patients was associated with presence of 1q21 amplification or t(4;14), which have been previously described as unfavorable prognostic factors for MM. 41,42 The 'low/high' miR-744 and let-7e groups of MM patients were also observed to be clinically heterogeneous, which was demonstrated by different levels of albumin, creatinine, β2-microglobulin, LDH, hemoglobin and thrombocyte count between groups. As mentioned above, all listed parameters are known to be markers of tumor mass and disease activity.…”

Section: Discussionmentioning

confidence: 99%

Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nclassification. 22 In this study, a new serum miRNAs expression profile, potent enough to distinguish newly diagnosed MM and MGUS patients from healthy controls, was created based on TaqMan Low Density Arrays (TLDA). This profile was validated by quantitative realtime PCR (qPCR) on a larger cohort of newly diagnosed and relapsed MM as well as MGUS patients. Moreover, miRNAs levels were correlated with clinical, biochemical and cytogenetic characteristics and survival data. Methods Patients and healthy donorsPeripheral blood (PB) serum samples from 103 newly diagnosed MM patients, 18 MM patients in relapse, 57 MGUS and 30 healthy donors (HD) from the Faculty Hospital Brno, Czech Republic, were obtained for this study. PB serum samples were collected as follows: centrifugation 3500 rpm/15 min/20°C. Samples were frozen as 0.5 mL aliquots, stored at -80°C and thawed only once. For 70 MM and 36 MGUS samples, BMPCs were obtained for routine interphase fluorescence in situ hybridization analysis (I-FISH), as described previously. 23 Patients' and donors' characteristics are described in Table 1 and in the Online Supplementary Table S1. For 6 newly diagnosed MM patients, BMPCs and exosomal and non-exosomal fraction from PB serum were collected. All patients signed an informed consent form approved by the hospital ethical committee before enrollment into this study. MiRNA extractionTotal RNA enriched for miRNAs was extracted from all serum samples using miRNeasy Kit (Qiagen) modified for circulating miRNAs according to the manufacturer's instructions. MiRNA/RNA quantity was assessed on a NanoDrop ND-1000 Spectrophotometer (Thermo Scientific) as measurement of each sample 2 times with mean SD=0.292 ng/μL. All samples fit into the Nanodrop ND-1000 validated measuring range. Exosomes precipitationExosomes were collected using ExoQuick Exosome Precipitation Solution (System Biosciences). Serum samples were centrifuged for 3500 rpm/10 min/4°C, 250 μL of serum was combined with 63 μL of ExoQuick, incubated for 30 min/4°C and centrifuged for 2 min/13000 rpm. Exosomal and non-exosomal fraction was used for miRNA/RNA extraction, as described above. TaqMan Low Density ArraysMegaplex profiling using human TaqMan Low Density miRNA Arrays A+B, v3.0 (TLDA) (Life Technologies) was performed to evaluate the expression of 667 miRNA (see Online Supplementary Methods). QPCR was performed on the ABI7900HT system; raw data were analyzed using SDS software v.2.3, RQ Manager v1.2.1 (Life Technologies). Candidate miRNA confirmation by qPCR and quantification of miRNAIndividual TaqMan miRNA assays for 6 miRNA (hsa-miR-222-002276, hsa-miR-744-002324, hsa-miR-130a-000454, hsa-miR34a-000426, hsa-let-7e-002406, hsa-let-7d-002283, Life Technologies) were used for qPCR on a 7500 Real-Time PCR System. QPCR and reverse transcription was performed following the manufacturer´s recommendations (see Online Supplementary Methods). Absolute quantification to determine the copy number of each miRNA per 1...

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“…The following chromosomal abnormalities with presumed impact on the prognosis of MM 16,17 were studied: RB1 deletion, p53 deletion, IgH gene disruption, translocation t(4;14), amplification 1q21 and hyperploidy. No differences were shown in the incidence of any of these chromosomal abnormalities between EM patients and those without EM (Table 5).…”

Section: Resultsmentioning

confidence: 99%

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse

et al. 2013

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Even in the era of new drugs, multiple myeloma patients with extramedullary relapse have a poor prognosis. Our goal was to analyze the frequency and outcome of extramedullary relapse occurring in relapsed multiple myeloma patients. In total, we analyzed the prognosis of 226 relapsed multiple myeloma patients treated between 2005 and 2008 and evaluated them for presence of extramedullary relapse. We found evidence of extramedullary relapse in 24% (55 of 226) of relapsed multiple myeloma patients. In 14% (32 of 226) of patients, the lesions were not adjacent to the bone, while extramedullary relapse adjacent to the bone was documented in 10% (23 of 226) of cases. Patients without extramedullary relapse had significantly longer overall survival than patients with extramedullary relapse (109 vs. 38 months; P<0.001). Moreover, patients with soft tissue-related extramedullary relapse had significantly poorer overall survival compared to bone-related extramedullary relapse patients (30 vs. 45 months; P=0.022). Also, overall survival from diagnosis was as low as five months for soft tissue-related extramedullary relapse patients when compared to 12 months overall survival for bone-related extramedullary relapse. This is the first study that shows a significant difference in prognosis for different types of extramedullary relapse. If the extramedullary myeloma infiltration was not bone-related, overall survival after relapse was extremely short (5 months). Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse

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Gain of 1q21 Is an Unfavorable Genetic Prognostic Factor for Multiple Myeloma Patients Treated with High-Dose Chemotherapy

Cited by 64 publications

References 32 publications

Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation

Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation

Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse

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