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The prognostic significance of monoclonal immunoglobulin gene rearrangement in conjunction with histologic B-cell aggregates in the bone marrow of patients with diffuse large B-cell lymphoma.

ABSTRACT: Bone marrow involvement (BMI) is a well-known poor prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL). This study robustly investigated the significance of monoclonal immunoglobulin gene rearrangement combined with histologic B-cell aggregates in bone marrow (BM) in the detection of a poor prognostic group. Pretreatment BM samples of 394 DLBCL patients were analyzed via the immunoglobulin gene rearrangement study and the microscopic examination. Monoclonal immunoglobulin gene rearrangement was detected in 25.4% of cases. Histologic B-cell aggregates with the features of large B-cell lymphoma aggregates, small cell B-cell lymphoma aggregates, or B-cell aggregates of unknown biological potential were observed in 12% of cases (6.9%, 1.3%, and 3.8%, respectively). Histologic B-cell aggregates were more associated with monoclonality than polyclonality. Cases with both monoclonality and histologic B-cell aggregates demonstrated close association with poor prognostic factors such as a higher International Prognostic Index score and showed an inferior overall survival rate when compared to cases with only monoclonality or only histologic B-cell aggregates. From the findings, a combination of monoclonality and histologic B-cell aggregates within the bone marrow was highly associated with poor prognosis and could be used to determine high-risk DLBLC patients with greater sensitivity and specificity than conventional microscopic examination or immunoglobulin gene rearrangement study alone.

SUBMITTER: Cho YA

PROVIDER: S-EPMC4924364 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The prognostic significance of monoclonal immunoglobulin gene rearrangement in conjunction with histologic B-cell aggregates in the bone marrow of patients with diffuse large B-cell lymphoma.

Cho Yoon Ah YA Yang Woo Ick WI Song Jae-Woo JW Min Yoo Hong YH Yoon Sun Och SO

Cancer medicine 20160229 6

Bone marrow involvement (BMI) is a well-known poor prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL). This study robustly investigated the significance of monoclonal immunoglobulin gene rearrangement combined with histologic B-cell aggregates in bone marrow (BM) in the detection of a poor prognostic group. Pretreatment BM samples of 394 DLBCL patients were analyzed via the immunoglobulin gene rearrangement study and the microscopic examination. Monoclonal immunoglobulin ge ...[more]

PMID: 26923640

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Project description:BACKGROUND: Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients. METHODS: We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients. RESULTS: Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 16.5% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, = 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis. CONCLUSIONS: We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.

Project description:Fibroblasts are a key cellular component of tumour microenvironment, along with other stromal cells playing a critical role in disease initiation and progression (1). In this study, bone marrow fibroblasts deriving from patients with monoclonal gammopathy of undetermined significance (MGUS) or active multiple myeloma (MM) were subjected to global gene expression analysis, in order to identify progression-associated alterations of gene expression. Through immunoselection procedures, primary coltures of bone marrow fibroblasts were established from bone marrow aspirate of 18 patients fullfilling the International Myeloma Working Group diagnostic criteria for MM (n=10) and MGUS (n=8). Differentially expressed genes were investigated through cDNA microarray (21,329 70-mer oligonucleotides; dual-label competitive hybridization), using the reference design as experimental protocol and t-test statistics for identifying differentially expressed genes. A number of genes functionally involved in survival, proliferation, motility, inflammation and angiogenesis were found to be up-regulated in bone marrow fibroblasts from MM patients with respect to MGUS patients. In parallel, several genes were down-regulated in MM fibroblasts. Overall, bone marrow fibroblasts from MM patients show a distinct gene expression pattern that differentiates them from bone marrow fibroblasts of MGUS. The observation of differentially expressed genes indicates an activation state of fibroblasts in MM, which very likely concur to determine a microenvironment supporting disease progression. 1) 1. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392 â401. Bone marrow fibroblasts deriving from patients with monoclonal gammopathy of undetermined significance (MGUS) and active multiple myeloma (MM), were provided by A.Vacca, (Department of Biomedical Sciences and Human Oncology, UniversitÃ degli Studi di Bari Aldo Moro, Italy). Briefly, primary coltures of bone marrow fibroblasts were established through immunoselection procedures on aspirates of 18 patients fullfilling the IMWG diagnostic criteria for active MM (n=10) and MGUS (n=8). Total RNA was extracted from each primary culture (test samples), and 1 Î¼g-aliquots of RNA from MGUS samples were pooled to obtain the reference RNA. Linear amplification of mRNA and fluorescent labelling of cDNA targets (Cy5, MM and MGUS test samples; Cy3, reference RNA) were performed by using the Amino Allyl MessageAmp II aRNA Amplification Kit (Ambion), and examined on Micro-CRIBI Human Oligo Array (Operon V2.0) microarrays. Array scanning was carried out using a VersArray ChipReaderÂ® 5Î¼m dual confocal laser scanner with VersArray ChipReader v3.1 analysis software , while row scanner images were analyzed with VersArray Analyzer Software v4.5 (Bio-Rad Laboratories) using media pixel intensities for each spot. Global background was subtracted by biquadratic polynomial approximation, and cross-channel normalization was performed by local regression (LOESS); logarithmic transformation was then performed for each expression level.

Dataset Information

The prognostic significance of monoclonal immunoglobulin gene rearrangement in conjunction with histologic B-cell aggregates in the bone marrow of patients with diffuse large B-cell lymphoma.

Publications

The prognostic significance of monoclonal immunoglobulin gene rearrangement in conjunction with histologic B-cell aggregates in the bone marrow of patients with diffuse large B-cell lymphoma.

Similar Datasets

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