Pathogenesis and progression of monoclonal gammopathy of undetermined significance

Bladé, Joan; Rosiñol, Laura; Cibeira, Ma Teresa; Larrea, Carlos Fernández de

doi:10.1038/leu.2008.203

Cited by 84 publications

(65 citation statements)

References 60 publications

(104 reference statements)

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“…In reference to MGUS, the molecular basis of its evolution to a malignant monoclonal gammopathy remains poorly understood (3). Different predictors of risk progression (size of M protein, type of immunoglobulin, BMPCI, serum free light chain ratio) have emerged, and there is growing evidence that the stromal component of the BM microenvironment may also play an important role in disease evolution (3,30).…”

Section: Discussionmentioning

confidence: 99%

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Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Panero

Arbelbide

Fantl

et al. 2010

Mol Med

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In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.

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Section: Discussionmentioning

confidence: 99%

“…After a median of 10 years, about onequarter of MGUS patients develop MM. Recent studies have identified markers that can be used to identify patients with high risk of progression: higher levels of monoclonal protein, non-IgG protein isotype and abnormal ratio of free light chains (3).…”

Section: Introductionmentioning

confidence: 99%

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Panero

Arbelbide

Fantl

et al. 2010

Mol Med

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“…However, after accounting for competing causes of death, true life-time probability of progression is lower (11%). 8 The risk of progression with MGUS does not diminish over time Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that is associated with a lifelong risk of multiple myeloma. We conducted a systematic review of all studies investigating the prevalence and incidence of MGUS in the online database PubMed.…”

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confidence: 99%

Prevalence of Monoclonal Gammopathy of Undetermined Significance: A Systematic Review

Wadhera

Rajkumar

2010

Mayo Clinic Proceedings

138

104

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M onoclonal gammopathy of undetermined significance (MGUS) is a premalignant, asymptomatic disorder characterized by monoclonal plasma cell proliferation in bone marrow with absence of end-organ damage. 1 Although historically considered a benign condition, patients with MGUS have a lifelong risk of multiple myeloma, an incurable plasma cell malignancy with a median survival of approximately 4 to 5 years. [2][3][4] Patients with MGUS are also at risk of related disorders, such as light-chain amyloidosis and macroglobulinemia. Conditions such as osteoporosis, hip fractures, and peripheral neuropathy are also associated with MGUS. 5 The rate at which MGUS progresses to multiple myeloma or a related disorder is 1% per year. 6,7 The probability of progression at 25 years of follow-up is approximately 30%. However, after accounting for competing causes of death, true life-time probability of progression is lower (11%). 8 The risk of progression with MGUS does not diminish over time Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that is associated with a lifelong risk of multiple myeloma. We conducted a systematic review of all studies investigating the prevalence and incidence of MGUS in the online database PubMed. The review was conducted from January 6, 2009, through January 15, 2010. The following MeSH search headings were used: monoclonal gammopathy, benign and prevalence; monoclonal gammopathy, benign and incidence; paraproteinemia and prevalence; and paraproteinemia and incidence. Articles were limited to those written in English and published by January 2009. Fourteen studies that met prespecified criteria were included and systematically assessed to identify the most accurate prevalence estimates of MGUS based on age, sex, and race. On the basis of our systematic review, we estimate that the crude prevalence of MGUS in those older than 50 years is 3.2% in a predominantly white population. Studies in white and Japanese populations demonstrate a clear increase in prevalence with age. The prevalence is also affected by sex: 3.7% and 2.9% in white men and women, respectively; and 2.8% and 1.6% in Japanese men and women, respectively. Additionally, MGUS is significantly more prevalent in black people (5.9%-8.4%) than in white people (3.0%-3.6%). We conclude that MGUS is a common premalignant plasma cell disorder in the general population of those older than 50 years. The prevalence increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. These results are important for counseling, clinical care, and the design of clinical studies in high-risk populations. and persists even in patients whose condition has remained stable for decades. 7,9 This fixed risk of progression regardless of duration of disease suggests a random 2-hit model of progression rather than a cumulative damage accumulation model in which the risk of progression would be expected to increase with duration of MGUS. The main risk factors for progressio...

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“…The laboratory should supply all available information with careful interpretation and consultation with the haematologist is recommended to decide on further laboratory and clinical investigations. If, for example, MGUS is diagnosed based on these results, there is an increased risk for the developing malignancy and these patients should be monitored regularly (28).…”

Section: Discussionmentioning

confidence: 99%

Quantitation of serum free light chains does not compensate for serum immunofixation only when screening for monoclonal gammopathies

Böer

Deufel

2009

Clinical Chemistry and Laboratory Medicine

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Background: Detection of plasma cell dyscrasias (PCD) requires screening of serum and urine for monoclonal proteins. Several studies have demonstrated increased sensitivity and specificity when measurement of serum free light chain (SFLC) is part of the screening protocol. In addition, omission of immunofixation (IFE) in the standard work-up that includes SFLC assay has been proposed. This study attempts to define the role of the SFLC assay in a screening strategy limited to serum only. It compares outcomes to a serum-only screening strategy that omits serum IFE. Methods: Serum from 691 patients was analysed for the presence of monoclonal protein using standard serum IFE, serum protein electrophoresis (SPE) and measurement of SFLC. Data were analysed retrospectively. Results: Specificity and sensitivity of abnormal SFLCratios for the detection of monoclonal protein using IFE were 96% and 41%, respectively. Eighteen patients with negative monospecific and Bence Jones IFE, but abnormal SFLC-ratios were identified. In most cases, this could be attributed to kidney and inflammatory disease or haematological disorders. In four cases, this resulted in further diagnostic investigation and light chain disease was later detected in two cases. Light chain disease was confirmed in one case but not confirmed in the other patient. In 14 patients, Bence Jones IFE was negative, although the concentrations of SFLC suggested the presence of monoclonal Bence Jones protein at concentrations detectable by IFE. Thus, either the anti-serum failed at detection, there was polymerisation of the free light chains or the SFLC assay overestimated protein concentrations. Simulating a work-up that included IFE only if abnormalities were detected by SPE or the SFLC assay would have resulted in 26% fewer IFEs being performed, but three patients with monoclonal proteins by IFE would have been missed. Conclusions: Abnormal SFLC concentrations are neither sensitive nor specific for the detection of

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Pathogenesis and progression of monoclonal gammopathy of undetermined significance

Cited by 84 publications

References 60 publications

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

Prevalence of Monoclonal Gammopathy of Undetermined Significance: A Systematic Review

Quantitation of serum free light chains does not compensate for serum immunofixation only when screening for monoclonal gammopathies

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