POLYMORPHISMS WITHIN AUTOPHAGY-RELATED GENES AS SUSCEPTIBILITY BIOMARKERS for MULTIPLE MYELOMA: A META-ANALYSIS of THREE LARGE COHORTS.

Abstract

Background: Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. Method(s): We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1x10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). Result(s): After meta-analysis of genetic data from three independent cohorts of European ancestry including 13387 subjects (6863 MM patients and 6524 controls), we identified six loci, ULK4, IKBKE, ATG5, CD46, CDKN2A, and PARK2, associated with MM risk (p=4.79x10-4~ 5.82x10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating levels of vitamin D3 (p=4.0x10-4), whereas the IKBKErs17433804 SNP correlated with levels of transitional CD24+CD38+ B cells (p=4.8x10-4) and circulating serum levels of MCP-2 (p=3.6*10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3-B cells, CD5+IgD-cells, IgM-cells, IgD-IgM-cells, and CD4-CD8-PBMCs (p=4.9x10-4-8.6x10-4) and circulating levels of IL20 (p=0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27-cells (p=9.3x10-4). Conclusion(s): This study reports the consistent association of genetic polymorphisms within the ULK4, ATG5, CDKN2A, IKBKE, CD46 and PARK2 loci in modulating MM risk and provides new insights into the functional role of ULK4, IKBKE, CD46, and CDKN2A polymorphisms in disease pathogenesis. Additional studies are still necessary to confirm the functional impact of these SNPs on the risk of developing MM and to identify the biological mechanisms behind the ATG5 association.