Abstract 1169: Paratarg-7, the first autosomal-dominantly inherited risk factor for hematological malignancies: single nucelotide poylmorphism- and microsatellite-based genome-wide linkage analysis

Abstract

Abstract Background: Antigenic targets of paraproteins in monoclonal gammopathy of undetermined significance (MGUS), multiple Myeloma (MM) and Waldenstrom's macroglobulinemia (WM) might play a role in the pathogenesis of these neoplasms by chronic antigenic stimulation, but very few have been identified, of which most were specific for one individual paraprotein only. In contrast, we recently described paratarg-7, a protein of unknown function which is expressed in all human tissues as the target of 15% of IgA and IgG paraproteins in MGUS and MM. Mutations or polymorphisms of paratarg-7 were not found, but hyperphosphorylation was detected in 35/252 (14%) of MGUS/MM patients and in 18/161 (11%) of WM patients, all of whom had an anti-paratarg-7 specific paraprotein. Analysis of 16 families demonstrated that hyperphosphorylated paratarg-7 is inherited in a dominant fashion and carriers of hyperphosphorylated paratarg-7 have an increased risk of developing MGUS/MM/WM (odds ratio 7.9; 95% CI: 2.8-22.6, p=0.0001). The aim of this study was to identify chromosome regions linked to hyperphosphorylated paratarg-7, a frequent antigenic target of paraproteins in MGUS/MM/WM. Methods: Serum and peripheral blood cells were obtained from 90 relatives of 16 families of patients with MGUS/MM/WM. We used a high density, single nucleotide polymorphism genotyping assay, the Illumina SentrixR BeadChip Array, the HumanHap300-Duo Bead Chip, comprising 318.000 tag single nucleotide polymorphisms to perform a genome-wide linkage analysis of 48 relatives of 4 families by filtering 23211 SNP markers with a spacing of > 100kb and an allele frequency > 0.15. Additionally, we carried out non-parametric as well as parametric analyses based on the genotypes of different microsatellite markers. Results: We found strong evidence for parametric linkage (full penetrant autosomal dominant model; disease marker allele frequency=0.02; LOD= 5.9) and non-parametric linkage (Zmean= 5.1; P<10−5) on chromosome 4q35. Conclusions: Hyperphosphorylated paratarg-7 is a highly significant risk factor for MGUS, WM and MM, with the highest odds ratio of any risk factor reported to date for these diseases. We report the first genome-wide linkage study of a new molecularly defined risk factor of MGUS//MM/WM and novel loci on 4q35 linked to hyperphosphorylated paratarg-7. Identification of novel causative genes for MGUS/MM/WM will now advance our understanding of the pathogenesis in these diseases. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1169.