Genomewide Linkage Screen for Waldenström Macroglobulinemia Susceptibility Loci in High-Risk Families

Abstract

Waldenstrom macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.

Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies

“…8 A number of affected families presenting multiple cases, as well as case-control and cohort studies, have been published showing familial clustering of LPL and WM. [9][10][11][12][13] Recently, based on data from a referral clinic with particular focus on familial disease, Treon et al reported that 19% of their WM patients had at least one first-degree relative affected with WM or another B-cell disorder. 13 To quantify risk estimates for familial aggregation in the general population, we recently performed a large population-based study, including 2,144 LPL/WM patients, 8,279 population-based matched controls, and linkable first-degree relatives of patients (n=6,177) and controls (n=24,609).…”

“…Additionally, a genome-wide linkage analysis of 11 families at high risk for WM found the strongest evidence of linkage on chromosomes 1q and 4q. 11 We have evaluated the familial risk of CLL in two studies. 15,19 Recently, a study including almost 10,000 CLL patients and their close to 27,000 first-degree relatives showed that first degree relatives of CLL patients had an 8.5-fold increased risk for CLL.…”

Molecular pathogenesis of Waldenstrom's macroglobulinemia

“…20 The rate of progression from IgM-MGUS to WM was further noted to be 1.5-2% a year. [21][22][23] While the development of WM is thought to be sporadic, there are a few studies demonstrating familial linkage and predisposition to the disease. 2,[24][25][26] Both familial clustering of WM and a notable increase (~10 fold) of IgM-MGUS frequency in first-degree relatives of WM patients is suggestive of familial risk.…”

“…49,50 While the clinical implications of trisomy 4 are not well understood, it has been suggested that 4q may play a role in increased susceptibility to WM. 21 In a genome-wide linkage analysis consisting of 122 individuals from 11 families identified as high-risk for WM, high non-parametric linkage was found on cytoband 4q33-q34, suggesting both linkage and common susceptibility between IgM-MGUS and WM patients. 21 The results of this single study lay the groundwork for further study of chromosome 4 and the potential role it plays in the etiology of WM.…”

“…27 Using the assumption that WM and IgM-MGUS share common susceptibility genes, strong linkages involving chromosomes 1q, 3q, and 4q have been identified. 21 A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested by the results of several studies. [14][15][16]28,29 Recently, it was shown that 11% of WM/IgM-MGUS reacted with paratarg-7 (P-7), a protein of unknown function.…”