Concept: Monoclonal gammopathy of undetermined significance
Risk of Acute Leukemia and Myelodysplastic Syndromes in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS): a Population-Based Study of 17 315 Patients
- Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
- Published over 5 years ago
The purpose of this study was to determine if there is an increased risk of acute leukemia and myelodysplastic syndromes (MDS) in persons with monoclonal gammopathy of undetermined significance (MGUS). We utilized a large population-based cohort of individuals systematically screened for the presence or absence of MGUS. MGUS status was then linked to the diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and MDS. 17 315 patients age 50 and older (605 MGUS and 16 710 controls) with a cumulative 435 021 person-years of follow-up were studied. MGUS patients had a significantly higher risk of developing MDS compared with controls, hazard ratio 2.4 (95%CI 1.08,5.32), P=0.031. There was no statistically significant increase in the risk of AML (RR 1.36 P=0.675), and no increased risk of developing ALL.Leukemia accepted article preview online, 5 February 2013; doi:10.1038/leu.2013.34.
High resolution digital imaging systems were recently introduced to capture and visualize serum protein electrophoresis results. In this study, we compared the performance of five, experienced interpreters using digital images and physical gels to identify and characterize monoclonal gammopathies by immunofixation.
Multiple myeloma in a dog with multiple concurrent infectious diseases and persistent polyclonal gammopathy
- Veterinary clinical pathology / American Society for Veterinary Clinical Pathology
- Published over 5 years ago
A 12-year-old, spayed female, mixed-breed dog was presented for acute hematuria, stranguria, polyuria, and polydipsia, as well as lameness for 8 days. Previous medical history included treatment for infection with Ehrlichia canis, Anaplasma phagocytophilum, Leishmania infantum, and Dirofilaria immitis 6.5 years prior to presentation. Besides persistently increased antibody titers to E canis and A phagocytophilum, polyclonal gammopathy with a monoclonal spike and moderate hypercalcemia were observed. There was marked hematuria, and Staphylococcus aureus was cultured from urine. Two weeks after successful treatment of the urinary tract infection, radiographs showed an extensive destructive monostotic lesion of the right humerus. Cytologic examination of fine-needle aspirates of this lesion revealed a neoplastic round cell population suggestive of multiple myeloma. The dog was treated with melphalan and prednisolone for suspected multiple myeloma and doxycycline for suspected ehrlichiosis and anaplasmosis. Treatments lead to resolution of the clinical signs, hypercalcemia, and monoclonal gammopathy, and there was radiographic improvement of bone lesions; polyclonal gammopathy persisted. About one year after presentation the dog was still in clinical remission. This is a rare report of a dog with suspected multiple myeloma and a history of multiple chronic infectious diseases, suggesting that chronic infection and uncontrolled long-term stimulation of the immune system could contribute to the pathogenesis of multiple myeloma.
The exact function of MAGE-C1/CT7 and MAGE-C2/CT10 is not yet understood in multiple myeloma (MM). However, the homologs MAGE-C1/CT7 and MAGE-C2/CT10 genes encode highly immunogeneic cancer/testis antigens (CTAs) and can be potential targets for T cell-based immunotherapy. MAGE-C1/CT7 and MAGE-C2/CT10 mRNA expression were investigated in MM patients, solitary plasmacytomas, monoclonal gammopathies of undetermined significance (MGUS) and bone marrow (BM) aspirates from healthy donors by RT-PCR. MAGE-C1/CT7 and MAGE-C1/CT10 were expressed in 67 and 59 % of the 46 MM analyzed patients. At least one of the genes was expressed in 76 % of MM cases. Solitary plasmacytoma also showed MAGE-C1/CT7 and MAGE-C2/CT10 expression. MAGE-C1/CT7 and MAGE-C2/CT10 were not expressed in normal BM samples, showing restricted expression of these CTA genes in MM, solitary plasmacytoma and MGUS. In the present study, we found high expression of the homologs MAGE-C1/CT7 and MAGE-C2/CT10 in monoclonal gammopathies and speculate whether these genes might represent a valuable therapeutic option for myeloma, in particular for combined immunotherapy.
The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.
Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents the results of a systematic review of the literature on the prevalence of monoclonal gammopathies and malignancies in Gaucher disease. A PubMed search identified 365 studies, of which 80 reported on concomitant Gaucher disease and malignancies and/or gammopathies (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population, Gaucher patients have an increased risk of cancer in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and multiple myeloma and haematological malignancies in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for hepatocellular carcinoma and renal cell carcinoma. Several factors have been hypothesized to play a role in the pathophysiology. These include: splenectomy, immune dysregulation, endoplasmic reticulum stress, genetic modifiers, altered iron metabolism and insulin resistance.
Serum immunoglobulin free light chain assay has proved to be an invaluable biological tool for diagnosis and monitoring of monoclonal gammopathies including multiple myeloma, primary amyloidosis, solitary plasmocytoma or monoclonal gammopathy of undetermined significance. Free light chain quantification, although essential, cannot be achieved by serum protein electrophoresis either because there is no monoclonal peak or because the peak is hidden in beta or alpha-globulin fraction. As for serum protein immunofixation, this major test allows the typing of the paraprotein but does not provide any quantitative evaluation. Hence, the development of free light chain assays constitutes a significant improvement in the management of these patients. In this context, we compared the results of serum free light chains quantification and of calculation of the ratio kappa/lambda, indicator of monoclonality, in forty samples performed on BN ProSpec(®) analyzer, with the two methods available on the European market. This comparative analysis provided evidence of a good correlation of results between the two methods. However, we noticed clinically significant differences in four samples. In addition, this evaluation highlighted the fact that all free light chain results must be biologically validated on the light of different criteria such as serum protein electrophoresis, serum protein immunofixation, presence of proteinuria, presence of renal failure, and additional clinical data, in order to ascertain the best interpretation for clinical use.
The daily productivity of a clinical laboratory depends on the large number of interferences that affect analytical accuracy. Obviously, they have always been considered as a very important aspect to keep accuracy under control. Nevertheless, we wondered if this aspect would be beneficial. In this article, we propose a method for finding monoclonal gammopathies that are based on the fact that the presence of paraprotein in the sample may interfere with routine laboratory assays, specifically, with the quantification of uric acid and conjugated bilirubin.
Multiparametric flow cytometry (MFC) is a useful tool for diagnosis of plasma cell dyscrasias and assessment of minimal residual disease (MRD) in plasma cell myeloma (PCM). However, the immunophenotypic differences between the clonal plasma cells (PCs) of plasma cell myeloma (PCM) and those of monoclonal gammopathy of undetermined significance (MGUS) as well as the correlation of these flow cytometric markers with pertinent laboratory parameters have not been evaluated.
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.