Differential characteristics of Waldenstrom macroglobulinemia according to patterns of familial aggregation
ABSTRACT Familial aggregation of Waldenström macroglobulinemia (WM) and related B-cell disorders (BCDs) suggests a role for genetic factors, but few data address environmental influences. We designed a questionnaire-based study to examine clinical and environmental factors in a cohort of WM families with various patterns of case aggregation. We analyzed data on 103 WM patients and 272 unaffected relatives from 35 multiple-case WM and 46 mixed WM/BCD kindred and 28 nonfamilial (sporadic) WM patients, using logistic regression models with generalized estimating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for association. In this study population, the WM disease process appeared similar among patients regardless of family history. Familial WM patients were more likely than unaffected relatives to report a history of autoimmune disease (OR, 2.27; 95% CI = 1.21-4.28) and infections (OR, 2.13; 95% CI = 1.25-3.64). Familial WM patients were also more likely to report exposure to farming (OR, 2.70; 95% CI = 1.34-5.42), pesticides (OR, 2.83; 95% CI = 1.56-5.11), wood dust (OR, 2.86; 95% CI = 1.54-5.33), and organic solvents (multiple-case WM OR, 4.21; 95% CI = 1.69-10.51) compared with unaffected family members. These data provide clues to both genetic and environmental factors that may influence development of WM. Well-designed case-control studies are needed to confirm these findings.
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ABSTRACT: Waldenström's macroglobulinemia (WM) is an indolent but incurable B-cell malignancy. Over the last decade, advances in the molecular field brought about by the use of high-throughput genomic analyses-including array-based comparative genomic hybridization and massively parallel genome sequencing-have considerably improved our understanding of the genetic basis of WM. Its pathogenesis, however, remains fragmented. Important steps have been made in elucidating the underlying aberrations and deregulated mechanisms of the disease, and thereby providing invaluable information for identifying biomarkers for disease diagnosis, risk stratification, and therapeutic approaches. We review the genetic basis of the disease.Current Oncology Reports 07/2013; DOI:10.1007/s11912-013-0331-7 · 2.87 Impact Factor
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ABSTRACT: Waldenström macroglobulinemia (WM) is a rare and currently incurable neoplasm of IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of the hematopoietic bone marrow with malignant lymphoplasmacytic cells. The symptoms of patients with WM can be attributed to the extent and tissue sites of tumor cell infiltration and the magnitude and immunological specificity of the paraprotein. WM presents fascinating clues on neoplastic B-cell development, including the recent discovery of a specific gain-of-function mutation in the MYD88 adapter protein. This not only provides an intriguing link to new findings that natural effector IgM(+)IgD(+) memory B-cells are dependent on MYD88 signaling, but also supports the hypothesis that WM derives from primitive, innate-like B-cells, such as marginal zone and B1 B-cells. Following a brief review of the clinical aspects and natural history of WM, this review discusses the thorny issue of WM's cell of origin in greater depth. Also included are emerging, genetically engineered mouse models of human WM that may enhance our understanding of the biologic and genetic underpinnings of the disease and facilitate the design and testing of new approaches to treat and prevent WM more effectively.01/2013; 2013:815325. DOI:10.1155/2013/815325
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ABSTRACT: Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10-5), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.PLoS ONE 06/2014; 9(6):e100691. DOI:10.1371/journal.pone.0100691 · 3.53 Impact Factor