Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

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. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) 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). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (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 = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be related to the occurrence of complications, including graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is connected with T lymphocytes, which identify alloantigens on host's antigen-presenting cells, activate production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and act on the immune effector cells and damage tissues and organs. AIM: The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT. METHODS: We enrolled 62 patients, i.e., 30 (48%) male and 32 (52%) female subjects [median age 49.5 (19-68) years], after allo-HSCT from siblings (n = 12) or unrelated donors (n = 50) due to acute myeloid leukemia with myeloablative conditioning (n = 26; 42%) and with non-myeloablative conditioning (n = 36; 58%). All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting. Blood samples were collected pre-transplant before and after (on day -1) the conditioning therapy and on days +2,+4, +6, +10, +20, and +30 after allo-HSCT. Serum levels of IL-2 and IFN-gamma were determined using ELISA. RESULTS: Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection. Group I included patients with neither acute GvHD nor infections [n = 15 (24%)], group II consisted of patients with infections without acute GvHD [n = 17 (27%)], group III was comprised of patients with acute GvHD without infections [n = 9 (15%)], and group IV included patients with both acute GvHD and infections [n = 21 (34%)]. IFN-gamma concentrations were higher in Group II than in other groups on days +20 (P = 0.014) and +30 (P = 0.008). Post-hoc tests showed lower concentrations of IFN-gamma on day +30 in groups I (P = 0.039) and IV (P = 0.017) compared to group II. The levels of IL-2 were mostly undetectable. CONCLUSION: Serum levels of IFN-gamma following allo-HSCT progressively escalate. High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD. Serum concentrations of IL-2 in most patients are undetectable.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Proinflammatory cytokines as potential risk factors of acute graft-versus-host disease and infectious complications after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with a risk of graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is related to T-lymphocytes, which identify alloantigens on host antigen-presenting cells, induce production of interferon (IFN) gamma and interleukin (IL)-2, recruit immune effector cells and destroy tissues and organs. MATERIAL AND METHODS: The study involved 62 patients, 30 (48%) men and 32 (52%) women [median age 49.5; (19-68) years] after myeloablative conditioning (MAC) n = 26 (42%) or reduced intensity conditioning (RIC) n = 36 (58%) therapy before allo-HSCT from a sibling (n = 12) or unrelated (n = 50) donor due to acute myeloid leukemia (AML). All patients received standard immunosuppressive therapy with cyclosporine A and methotrexate plus pre-transplant anti-thymocyte globulin in the unrelated transplant setting. Blood samples were collected pre-transplant before the start of and after conditioning therapy (1 day pre-transplant) and 2, 4, 6, 10, 20, 30 days following allo-HSCT. The analysis of potential risk factors included IL-2 and IFN-gamma concentrations, patients' age, the use of MAC/RIC and CR/non-CR status before transplantation. RESULTS: The statistical analysis revealed that independent risk factors for aGvHD included non-CR status before allo-HSCT [odds ratio (OR) = 10.52, P = 0.040], the use of MAC [hazard ratio (HR) = 4.80, P = 0.007] and a high level of IFN-gamma on day 6 post-transplant (HR = 1.03, P = 0.032). MAC was also the independent risk factor for infectious complications (OR = 4.04, P = 0.024). CONCLUSION: A high level of IFN-gamma on day 6 post-transplant, non-CR status before allo-HSCT and the use of MAC are independent risk factors for aGvHD. MAC is also the independent risk factor of infectious complications.

Cereblon (CRBN) gene polymorphisms predict clinical response and progression-free survival in relapsed/refractory multiple myeloma patients treated with lenalidomide: a pharmacogenetic study from the IMMEnSE consortium.

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.