Association of a dominantly inherited hyperphosphorylated paraprotein target with sporadic and familial multiple myeloma and monoclonal gammopathy of undetermined significance: a case-control study.

摘要

BACKGROUND: Chronic antigenic stimulation might have a role in the pathogenesis of monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma. The aim of this study was to search for factors underlying the autoimmunogenicity of paratarg-7, a frequent antigenic target of paraproteins in MGUS and multiple myeloma. METHODS: Between January, 2005, and February, 2009, serum and peripheral blood cells were obtained from consecutive patients with MGUS or multiple myeloma and healthy blood donors, and paratarg-7 was analysed by DNA sequencing, SDS-PAGE, isoelectric focusing, and western blotting. FINDINGS: Mutations or polymorphisms of paratarg-7 were not noted, but hyperphosphorylation was detected in 35 (13.9%) of 252 patients with MGUS or multiple myeloma, all of whom had an anti-paratarg-7-specific paraprotein. Analysis of eight families showed that hyperphosphorylated paratarg-7 is inherited in a dominant fashion, and that carriers of hyperphosphorylated paratarg-7 have an increased risk of developing MGUS and multiple myeloma (odds ratio [OR] 7.9, 95% CI 2.8-22.6; p=0.0001). INTERPRETATION: Familial MGUS and multiple myeloma were associated with a dominant inheritance of hyperphosphorylated paratarg-7, enabling family members at increased risk for MGUS or multiple myeloma to be identified. That only patients with MGUS or multiple myeloma who are carriers of hyperphosphorylated paratarg-7 had a paratarg-7-specific paraprotein suggests that the hyperphosphorylation of paratarg-7 induces auto-immunity and is involved in the pathogenesis of MGUS and multiple myeloma; for example, by chronic antigenic stimulation. FUNDING: Forderverein Krebsforschung Saar-Pfalz-Mosel e.V. (eingetragener Verein: officially registered charity) and HOMFOR (the research programme of the Saarland University Faculty of Medicine).