Genome-Wide Association Study for Waldenström Macroglobulinemia Identifies Novel Susceptibility Loci

Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. Family history is strongly associated with risk of WM, and the estimated heritability is high; however, the genetic basis for WM predisposition remains unknown. To identify susceptibility loci for WM, we conducted a two-stage genome-wide association study (GWAS) in over 500 WM/LPL cases and 4300 controls of European ancestry. In the discovery stage (stage 1), 217 unrelated WM cases (40% familial) and 3,798 controls were genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms. After quality control filtering, the data were imputed using the Haplotype Reference Consortium panel and analyzed using logistic regression. Eleven promising loci (P <5.0 x 10^-7) were selected for replication in 313 WM/LPL cases and 564 controls. Two novel loci were convincingly replicated in stage 2 (P<1.2 x 10^-5) and reached genome-wide significance in the combined analysis of both stages: 6p25.3 (EXOC2, OR=21.14, P=1.36 x 10^-54) and 14q32.13 (intergenic near TCL1, OR=4.90, P=8.74 x 10^-19). A possible second independent signal was observed at 14q32.13 but did not reach genome-wide significance (P=4.66 x 10^-7). When the analysis was limited to WM, results were slightly stronger but generally similar to those for WM/LPL combined. Dysregulated TCL1 expression in B cells enhances cell proliferation and survival, leading to cell transformation and mature B-cell tumors, and TCL1 has been shown to be aberrantly expressed in WM. EXOC2 interacts with Ral proteins to mediate oncogenic RAS signaling that is critical for cancer cell survival and proliferation. We found that cells transduced with the EXOC2 variant allele reporter pCS-EGFP-3'G showed significantly increased EGFP fluorescence compared to the wildtype, suggesting the variant is associated with increased EXOC2 protein levels. Cells harboring the EXOC2 variant allele were also observed to have significantly increased cell proliferation compared to wildtype cells. We further discovered that the E XOC2 variant abrogates a miRNA binding site, possibly contributing to gene expression changes for NF-κB pathway constituents. Together these newly discovered loci explain ~4% of the familial risk and suggest possible underlying biological mechanisms, significantly increasing our understanding of the genetic susceptibility of WM/LPL.