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Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

SUBMITTER: Greenberg AJ

PROVIDER: S-EPMC3369675 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

Greenberg Alexandra J AJ Rajkumar S Vincent SV Vachon Celine M CM

Blood 20120221 23

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk fact ...[more]

PMID: 22354002

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Project description:ImportanceMultiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup.ObjectiveTo longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS.Design, setting, and participantsThis prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018.Main outcomes and measuresSerum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured.ResultsOf 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P < .001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P < .001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P < .001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P < .001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P < .001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS.Conclusions and relevanceThe findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.

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

Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

Publications

Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

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