Inheritance in MGUS and MM.

Multiple myeloma (MM) is characterized by a clonal proliferation of malignant plasma cells in the bone marrow which secrete monoclonal immunoglobulins (paraproteins) into the serum. Clinical characteristics are lytic bone lesions, impairment of normal hematopoiesis and kidney function. It is accepted that all MM cases are preceded by an asymptomatic expansion of clonal plasma cells designated monoclonal gammopathy of undetermined significance (MGUS) [1]. Only a minority of individuals with MGUS evolve to symptomatic MM. The etiology of MGUS/MM is unknown and generally accepted risk factors are age > 65 years (odds ration [OR]: 12-16), male gender (OR: 1.5) and a positive family history (OR: 1.5-5.0) [2]. One hypothesis for the pathogenesis of MM is chronic antigenic stimulation; however, until recently the structures entertaining chronic antigenic stimulation remained largely unknown. To identify the antigenic targets of paraproteins (paratargs), protein macroarrays were used unmodified or after in-vitro sumoylation for screening of paraprotein-containing sera at a dilution of 1:10 7. With unmodified macroarrays 11 autoantigens were identified as the targets of paraproteins. Of these, one was an allo-antigenic paraprotein target (sperm-specific cylicin-2 in a woman with MM), one was a heteroantigen (porcine kinesin), while the remaining nine were autoantigens [3-5]. Of the nine autoantigens all except one (where no material was available) were hyperphosphorylated in patients compared to healthy controls as the most likely reason for their autoimmunogenicity, and in all these patients the hyperphosphorylated variant was inherited as a dominant trait. While most hyperphosphorylated paratargs were found only in few families, paratarg-7 was found in 15% of European, 4.5% of Japanese, and 37(!)% of all African-American MGUS/MM patients. Due to a lower prevalence of carriers of hyperphosphorylated paratarg-7 (pP-7) in the healthy population, the OR for a healthy pP-7 carrier for MGUS/MM varies between 13.1 in the Japanese, 7.9 in the European and 4.8 in the Afro-American population. Using sumoylated macroarrays, 12% of the paraproteins from European, 11% from African-American and 5% from Japanese patients reacted specifically with sumoylated heat shock protein-90β isoform-α (HSP90-SUMO). Similar to the findings with the hyperphosphorylated paratargs, all patients with HSP90-SUMO-binding paraproteins carried HSP90-SUMO and HSP90-SUMO carrier state is inherited as an autosomal-dominant trait. HSP90-SUMO is also a strong risk factor for MGUS/MM with an OR of 14.8 in Europeans, 6.2 in Japanese and 7.4 in African-Americans [6]. With pP-7 and HSP90-SUMO taken together, roughly 30% of the European and 50% of the African-American MGUS/MM patients, respectively, …