Chronic Infection, a Neglected Cause Of Development Of Monoclonal Gammopathy Of Undetermined Significance (MGUS) and Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3116-3116 ◽  
Author(s):  
Delphine Feron ◽  
Cathy Charlier ◽  
Pauline Lehebel ◽  
Denis Caillot ◽  
Cedric Rossi ◽  
...  
Keyword(s):  
Chronic Infection ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Core Protein ◽  
Lymphocytic Leukemia ◽  
Nuclear Antigen ◽  
Human Herpes Virus 8 ◽  
Epstein Barr ◽  
H Pylori ◽  
Undetermined Significance

Abstract Introduction Chronic infection can lead to B-cell malignancy via the direct transformation of infected B-lymphocytes or indirectly via cell transformation consecutive to chronic antigen-driven stimulation; the two mechanisms may occur simultaneously (Seifert et al. Methods Mol Biol 2013; 971:1; Hermouet et al. New Engl J Med 2003; 348:178; de Martel et al. Lancet Oncol 2012). Numerous studies have established that viruses (Epstein-Barr virus (EBV), human herpes virus 8, hepatitis C virus (HCV)) or bacteria (H. pylori) can induce lymphoma and chronic lymphocytic leukemia (CLL). In contrast, the role of chronic infection in the pathogenesis of myeloma is rarely investigated. Yet monoclonal immunoglobulins (mc Ig) that arise in HCV-positive myeloma patients typically target the virus (Bigot-Corbel et al. Blood 2008). Thus HCV infection may lead to monoclonal gammopathy of undetermined significance (MGUS) and eventually, myeloma. The present study shows that mc Ig also frequently target EBV, and less frequently, H. pylori. Methods In order to study the specificity of mc Ig, we designed a new assay based on a multiplexed infectious protein (MIP) microarray that combines representative panels of epitopes of a panel of germs that included HCV, EBV, H. pylori and 5 other germs, spotted in triplicate on nitrocellulose-coated slides (Feron et al. Anal Biochem 2013; 433:202). Slides were first incubated with either serum or purified mc Ig, then with an infrared dyed (IRD)-labeled secondary antibody, and fluorescence signals were detected and quantified. Results The specificity of purified mc Ig from 101 patients diagnosed with MGUS (n=34) or myeloma (n=67) was analysed using the 8-germ MIP microarray assay. We found that 20.6% of MGUS and 24.2% of myeloma patients (p=0.810) presented with a mc Ig that was specific for an antigen from HCV, EBV, or H. pylori. Indeed for 23/101 patients (22.7%), the purified mc Ig recognized HCV (n=10), EBV (n=11) or H. pylori (n=2). In contrast, none of the 101 mc Ig studied targeted CMV, a virus against which a majority of individuals possess antibodies. Interestingly, HCV- and EBV-specific mc Ig all targeted a single antigen. For 10/11 (91%) of the HCV-positive patients, the mc Ig was directed against HCV core protein. Regarding EBV-positive patients, the mc Ig specifically recognized EBV in 23% cases (11/59 tested), and in all cases the mc Ig targeted Epstein Barr nuclear antigen (EBNA). For 8% (2/25 tested) of H. pylori-positive patients, the mc Ig targeted different antigens of H. Pylori. The specificity of each mc Ig was confirmed by Western Blot analysis. Conclusion Altogether, 22.7% of the 101 MGUS and myeloma patients examined presented a mc Ig specific for HCV, EBV or H. pylori. Thus beside lymphoma and CLL, chronic infection by these 3 germs can also induce MGUS and eventually, trigger the pathogenic processes that lead to myeloma. Efforts should be made to identify the subsets of patients with mc Ig specific for HCV, EBV and H. pylori, preferably at the MGUS stage, as anti-infection treatment is expected to cure MGUS and prevent progression toward myeloma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prevalence of Monoclonal Gammopathy of Undetermined Significance in a Large Population with Annual Physical Examination in Beijing, China

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5519-5519
Author(s):  
Jinuo Wang ◽  
Jian-Hua Han ◽  
Yue-lun Zhang ◽  
Xin-xin Cao ◽  
Dao-Bin Zhou ◽  
...  
Keyword(s):  
Physical Examination ◽  
Light Chain ◽  
Chinese Population ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Large Population ◽  
M Protein ◽  
Monoclonal Protein ◽  
Significant Difference ◽  
Undetermined Significance

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic premalignant plasma cell disorder. Previous studies in Western countries have described the prevalence of MGUS in Caucasians. However, data is limited in Chinese population. We therefore performed this study to ascertain the prevalence and characteristics of MGUS among Chinese population. Methods A total of 154597 consecutive healthy participants from Beijing who underwent annual physical examination between December 2013 and April 2019 at Peking Union Medical College Hospital were enrolled. Serum M protein was evaluated by capillary electrophoresis. Patients with a positive or suspicious serum M protein were suggested to be referred to the hematological clinic for immunofixation electrophoresis (IFE) and free light chain (FLC) assays. MGUS was defined in accordance with previous definitions. We calculated age-specific and sex-specific prevalence and described laboratory characteristics of patients with MGUS among those participants. Results MGUS were diagnosed in 843 patients (0.55%, 95%CI 0.51% to 0.59%). The median age at presentation was 58 years, with a range of 25-96 years. The overall prevalence of MGUS was 1.14% among participants aged 50 years or older and 2.6% among those aged 70 years or older. In both sexes, the prevalence increased with age: 0.1% (<40 years), 0.36% (40-49 years), 0.78% (50-59 years), 1.28% (60-69 years), 2.19% (70-79 years), and 3.77% (≥80 years) separately (Figure 1). The prevalence among men were higher than that among women (0.67% vs. 0.40%, OR =1.719, 95% CI 1.490 to 1.983, P<0.001) (Figure 1). The median concentration of serum Monoclonal protein was 1.4 g/L (0.1 -27.8 g/L). M protein level was less than 0.5g/L in 220 patients (26.1%), less than 5 g/L in 81.1% and more than 15 g/L in only 1.9% of 843 persons. There was no significant difference in the concentration of the monoclonal protein among the age groups. Of the 519 patients who were tested for IFE, the isotype of the monoclonal immunoglobulin was IgG in 344 (66.3%), IgA 112 (21.6%), IgM in 48 (9.2%), IgD in 2 (0.4%), light-chain in 3 (0.6%) and biclonal in 10 (1.9%). The serum light-chain type was kappa in 260 (50.1%), lambda in 255 (49.1%) patients, while 4 patients (0.8%) with biclonal M protein have both kappa and lambda light-chain. Of the 180 people who were tested for FLC, 42 (23.3%) had an abnormal FLC ratio. IgG isotype, M protein <15 g/L and normal FLC ratio were found in 102 patients (56.7%) and the remaining 78 people (43.4%) had 1(30.6%) or 2(12.8%) abnormal factors. Conclusions MGUS was found in 1.14% of persons 50 years of age or older and 2.6% among those 70 years of age or older among healthy Chinese population. The prevalence of MGUS increases with age. Males have a higher frequency of MGUS than Females. These observations offer the overall situation of MGUS epidemiology in a large Chinese population. Disclosures No relevant conflicts of interest to declare.

Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

2002 ◽  
Vol 20 (6) ◽  
pp. 1625-1634 ◽  
Author(s):  
Clara Cesana ◽  
Catherine Klersy ◽  
Luciana Barbarano ◽  
Anna Maria Nosari ◽  
Monica Crugnola ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Extramedullary Plasmacytoma ◽  
Lymphocytic Leukemia ◽  
Cumulative Probability ◽  
Primary Amyloidosis ◽  
Smoldering Multiple Myeloma ◽  
Bence Jones Proteinuria ◽  
Undetermined Significance

PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression. PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution. RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P < .0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression. CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

Epstein–Barr virus infection is associated to patients with multiple myeloma and monoclonal gammopathy of undetermined significance

2016 ◽  
Vol 58 (2) ◽  
pp. 466-469 ◽  
Author(s):  
Giuseppe Mameli ◽  
Claudio Fozza ◽  
Magdalena Niegowska ◽  
Giovanna Corda ◽  
Maria Francesca Ruda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Virus Infection ◽  
Monoclonal Gammopathy ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Epstein Barr ◽  
Barr Virus Infection ◽  
Undetermined Significance

Splicing Mutations in the Hyaluronan Synthase I Gene of Patients with Monoclonal Gammopathy of Undetermined Significance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2841-2841
Author(s):  
Hemalatha Kuppusamy ◽  
Amanda Warkentin ◽  
Andrew Belch ◽  
Linda M. Pilarski
Keyword(s):  
Protein Sequence ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Hyaluronan Synthase ◽  
In Vitro Mutagenesis ◽  
Aberrant Splicing ◽  
Healthy Donors ◽  
Increased Risk ◽  
Recurrent Mutations ◽  
Undetermined Significance

Abstract Abstract 2841 Poster Board II-817 Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder. A small proportion of MGUS transform to multiple myeloma (MM) or other B lineage malignancies. Hyaluronan synthase I (HAS1) is overexpressed in many human cancers, including MM. Here we show that intron 3, a region involved in aberrant splicing of HAS1, is heavily mutated in 34 patients with MGUS. Aberrant splicing of HAS1 correlated with poor outcome in a cohort of MM patients. HAS1 is GC-rich and as such is likely to be subject to mutation events. We recently reported a series of nearly 200 HAS1 mutations in 17 MM and Waldenstrom's macroglobulinemia (WM) patients, that were absent from healthy donors (Adamia et al, Blood, 2008, 112:5111). Forty-nine of these HAS1 mutations were recurrent, defined as being present in more than one patient. None of them were present in sequenced regions of HAS1 from a small series of MGUS patients. Mutated HAS1 DNA directs aberrant splicing of HAS1 and in vitro mutagenesis of HAS1 intron 3 alters HAS1 splicing patterns (see abstract by Kriangkum et al.), mimicking the aberrant splicing seen in MM patients. To sequence HAS1 from a larger cohort, we developed a streamlined sequencing strategy that allowed rapid sequencing of exon 3 and intron 3, regions of the HAS1 gene rich in mutations. Our objective was to identify HAS1 mutations in MGUS as compared to a larger cohort of MM and healthy donors. Many reports have shown familial clusters of MGUS and MM and of other B cell malignancies involving MGUS, supporting the idea that genetic factors, and possibly genetic predispositions, contribute to the development of disease. Patients and Methods: We sequenced HAS1 regions from 34 MGUS patients, 50 MM patients, and 45 healthy donors. In all cases, we sequenced an 850 bp region covering exon 3 and intron 3 of the HAS1 gene. For each patient, we sequenced eight HAS1 region subclones, in both directions. To predict impact of recurrent HAS1 mutations on the splicing process, we performed in silico analysis using online bioinformatic tools. Results: To date we have identified, 117 HAS1 mutations in HAS1 gene in MGUS patients including 5 frequently detected NCBI single nucleotide polymorphisms (SNPs). Although the same NCBI SNPs were also identified in healthy donors, increased homozygosity was detected in MGUS patients compared to healthy donors. Overall, among the novel HAS1 mutations, 32 (27%) were shared between MGUS and MM but absent in healthy donors, defining them as recurrent. Seven of the 32 mutations (23%) shared between MGUS and MM were recurrent in 2-3 individual MGUS patients; three of the recurrent MGUS mutations were missense mutations present in the coding region of exon 3, changing the protein sequence. Our initial bioinformatic analysis showed that the two of the shared recurrent mutations were found in the SR protein binding sites of the pre-mRNA and may contribute to aberrant splicing of the primary HAS1 transcript. We predict that our ongoing analysis HAS1 mutations in MGUS patients will identify a subpopulation(s) at high risk of aberrant splicing and thus at increased risk of transformation to overt MM. Conclusion: HAS1 appears to be hypermutated, perhaps due to its GC-rich nature. HAS1 mutations were identified in patients with a clinical diagnosis of MGUS (range of 1-14 mutations per MGUS). Thirty-two HAS1 mutations were recurrent in MGUS and MM but were absent from healthy donors. Some of these mutations are predicted to have functional significance for protein sequence and pre-mRNA splicing, possibly leading to increased risk for or predisposition to disease. Although genetic background and environmental context are likely to be important factors, our report of novel mutations in HAS1 of MM and WM patients, confirmed now in MGUS, suggests that mutations in HAS1 may play a key role in oncogenesis. Further genetic analysis of patient populations and the biochemical characterization of the mutated proteins will provide considerable insight into the function of HAS1 during transformation from MGUS to overt MM. Disclosures: No relevant conflicts of interest to declare.

Obesity is Associated with a 2-Fold Elevated Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) Among African-American and Caucasian Women.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4876-4876
Author(s):  
Ola Landgren ◽  
Vincent Rajkumar ◽  
Ruth Pfeiffer ◽  
Robert Kyle ◽  
Jerry Katzmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
African Americans ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Pearson Correlation ◽  
Elevated Risk ◽  
Caucasian Women ◽  
Undetermined Significance

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

Elevated Rates of Monoclonal Gammopathy in High-Risk Chronic Lymphocytic Leukemia Pedigrees

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1449-1449
Author(s):  
Nicola J Camp ◽  
Rosalie G Waller ◽  
Cassandra Garner ◽  
Guido J Tricot ◽  
Michael Tomasson ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Clinical State ◽  
Light Chains ◽  
Solid Cancer ◽  
Monoclonal Gammopathies

Abstract High-risk pedigrees can be a powerful design for disease gene discovery. Understanding tumor spectrum in high-risk pedigrees optimizes power for discovery, allows meaningful assessment of segregation and determination of familial risk. Many studies have observed that different hematological malignancies co-aggregate in families. In particular, we previously performed genealogical cluster analysis in the Utah Population Database and identified significant co-aggregation between chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We have also determined that the frequency of the pre-clinical state, monoclonal B-cell lymphocytosis (MBL), is elevated in high-risk CLL pedigrees. Here, we explore evidence for monoclonal gammopathies in high-risk CLL pedigrees using serum immunoglobulin (Ig) biomarkers. Monoclonal gammopathies are characterized by a clonal expansion of plasma cells that secrete a monoclonal Ig. We used two serum biomarker tests to indicate the existence of clonal Ig proteins: Freelite™ and Hevylite™ immunoassays. These were performed on 498 frozen serum samples: 163 population controls; 97 MM/MGUS cases; 114 CLL cases (91 sporadic CLL and 23 from high-risk pedigrees); and 124 relatives in CLL pedigrees. Freelite detects and quantitates free light chains (κ and λ). Hevylite detects and quantitates specific immunoglobulins (IgA, IgG or IgM) bound to specific light chains. We determined monoclonality if either assay indicated an abnormal κ/λ ratio (specifically in conjunction with increased total Ig-type for Hevylite).The majority of monoclonality identified (92%) included restricted free lights chains. Those involving monoclonal Ig heavy chains only were all positively confirmed by standard serum protein and/or immunofixation electrophoresis. We observed a background of monoclonal gammopathy in our control samples (5/163, frequency =0.031), consistent with the advanced age of this comparison set (average 67y). As expected, monoclonal gammopathy was evident in the MM/MGUS cases (38/97, frequency=0.392, p=3.5×10-14), which increased to frequency=0.732, for abnormal κ/λ ratio considered without requiring increase of the specific Ig-type for Hevylite. The absence of complete identification is likely due to our samples being from prevalent cases at different treatment stages, in addition to non-secretory disease. The CLL cases (sporadic or pedigree) exhibited very similar rates of suggested monoclonal gammopathy (together 43/114, frequency=0.377, p=6.5×10-14). Pedigree relatives also exhibited evidence of clonal Ig proteins (9/124, frequency=0.073). The frequency across all relatives was not statistically different than the control set; however, the relatives were substantially younger than controls (minimum age 20y). When relatives were restricted to those over 49y (with average 67y), the frequency increased to 0.095 and became statistically increased compared to controls (p=0.028). The 9 relatives with monoclonality were: 1 non-Hodgkin lymphoma NOS, 1 MBL case, 2 solid cancer cases, and 5 relatives with no known cancer diagnoses. In conclusion, using sensitive Ig biomarkers we find that individuals in high-risk CLL pedigrees are at a greater risk of monoclonal gammopathy than the general population. This observation is consistent with previous clustering results indicating co-aggregation and a possible genetic etiologic overlap between CLL and MM. Furthermore, these Ig quantitative measures offer detailed phenotypes for all pedigree members, creating more informative pedigrees, increasing the power for gene identification. These measures offer an avenue for exploiting similarities across B-cell malignancies and have the potential to improve our ability to identify at-risk individuals. Disclosures No relevant conflicts of interest to declare.

Abnormal Seroresponse to Common Viruses in CLL RAI0

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5632-5632
Author(s):  
Silvia de Sanjosé ◽  
Claudia Robles ◽  
Tim Waterboer ◽  
Delphine Casabonne ◽  
Angelika Michel ◽  
...  
Keyword(s):  
Viral Infections ◽  
Conflicts Of Interest ◽  
Genome Project ◽  
Additive Models ◽  
Lymphocytic Leukemia ◽  
Logistic Regression Models ◽  
Barr Virus ◽  
Epstein Barr ◽  
Population Controls ◽  
Control Study

Abstract Background: Chronic Lymphocytic Leukemia (CLL) has been related to an increased susceptibility to infections particularly in advanced stages. Evidence is accumulating of an immune impaired response at early stages that could affect prognosis. We evaluated the pattern of seroresponse to common infections in CLL Rai0 cases and in general population controls. Methods: A case-control study within the multicase-control study (MCC Spain) and the International Cancer Genome Consortium (ICGC) was designed. 204 CLL cases, 69.6% newly diagnosed and 30.4% prevalent, and 370 population controls matched by sex, age and recruitment area were analyzed. All subjects provided a blood sample and answered a personal interview. In addition to socio-demographic, behavioral and medical characteristics for cases and controls, data on CD38, ZAP70 and common CLL deletions were available for analysis. Seroreactivities against the antigens from JC polyomavirus (JCPyV; VP1), Merkel cell poliomavirus (MCPyV; VP1), herpes simplex 1 (HSV1; gB), Epstein-Barr virus (EBV;zebra, EBNA, EA-D and VCAp18) and cytomegalovirus (CMV;­ pp150, CM2, pp52, pp28 and pp65) were measured using bead-based multiplex serology technology. Multivariate logistic regression models were used to examine seroprevalence to different viral infections and seroreactivity intensity (in tertiles) in cases and controls. Generalised additive models were used to explore seroreactivity patterns. Results: Seropositivity was very high in both cases and controls and was significantly higher for all infections tested among controls: HSV1 92.0% cases vs. 94.4% controls; CMV 84,4% vs. 88,3%; EBV 97,5% vs. 98,9%; JCPyV 56.6% vs. 68.9% and MCV 81.4% vs. 83.4%. Among seropositive subjects, a statistically significant decrease in antibody response was observed among CLL cases compared to controls (HSV-1 p<0.009; EBV_EBNA, p<0.000; CMV overall, p<0.0279; CMV_pp28, p<=0.001). No changes in the estimates were observed when adjusting for family history, smoking, or alcohol intake. Increased antibodies to EBV and CMV lytic antigens were detected among cases compared to controls for both EA_EBV (OR=1.36, 95%CI=0.8-2.2) and pp65_CMV (OR=1.42, 95%CI=0.9-2.3).Survival analysis is ongoing and results will be presented. Conclusions: CLL Rai0 cases showed a reduced ability to mount or maintain seroresponses against common viral infections. Despite this immune suppression, increased antibody titers to EBV and CMV lytic antigens were present indicating a response to reactivated infections; this could potentially be an early sign of CLL. This work was partially supported by the Spanish Ministry Council: PI11/01810, PI11/02213, the ICGC CLL-Genome Project is supported by Spanish Ministerio de Economía y Competitividad (MINECO) and the Red Temática de Investigación del Cáncer [RTIC RD12/0036/0036]. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 791-795 ◽  
Author(s):  
Ola Landgren ◽  
Sigurdur Y. Kristinsson ◽  
Lynn R. Goldin ◽  
Neil E. Caporaso ◽  
Cecilie Blimark ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Monoclonal Gammopathy ◽  
Case Reports ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Degree Relative ◽  
First Degree Relatives ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk ◽  
Undetermined Significance

Abstract Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

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