Contributions
Abstract: PB1938
Type: Publication Only
Background
Monoclonal gammopathies (MG) are a group of disorders characterized by the proliferation of monoclonal plasma cells, which produce and secrete monoclonal immunoglobulin (M protein). Symptomatic multiple myeloma (MM) is characterized by the clonal proliferation of plasma cells. MM is consistently preceded by a pre-neoplastic entity, called monoclonal gammopathy of undetermined significance (MGUS), with an intermediate phase of indolent multiple myeloma (MMI). This disease is a heterogeneous hematological neoplasm characterized by the proliferation of clonal, long-lived plasma cells within the bone marrow (BM) secreting monoclonal proteins and by the presence of so-called CRAB criteria and/or biomarkers of malignancy (as clonal BM plasma cells ³ 60%, involved:uninvolved serum free light chain ratio ³100, >1 focal lesion in MRI studies). Genetic instability and several molecular abnormalities are hallmarks of MM cells. Alterations in DNA repair pathways, namely abnormal activity of non homologous end–joining (NHEJ) repair pathway, are involved in the disease onset and progression. Moreover, it has been observed that virtually all primary MM samples have constitutive nuclear factor-κB (NF-κB) pathway activity, having this pathway a well–established role in MM pathogenesis.
Aims
In this context, we hypothesized that polymorphisms of genes involved in NHEJ repair pathway (XRCC5, XRCC4) and in NF-κB pathway (NFKB2, and BIRC5) may have impact in MG susceptibility and prognosis.
Methods
In the present, a hospital-based case-control study, we analyzed eight polymorphism in four genes (XRCC5, XRCC4, NFKB2, and BIRC5), by genotyping 189 individuals (63 MG patients and 126 controls) using TaqMan qPCR. Results are expressed in terms of frequencies of allele, genotype, haplotype, and genotypic profiles, and their correlation with MG susceptibility. The strength of association between polymorphisms and disease risk was assessed by odds ratio (OR) with 95% confidence interval (CI95%) calculated by logistic regression. We also investigated the association of these SNPs with overall survival through Kaplan Meier curves. All statistical analyses had a significance levels of 95%.
Results
In the patient group, 51% (32/63) of the individuals were females and 49% (31/63) were males; the mean age was 70.11±10.25 years old. Among the control group, 52% (65/126) of the individuals were females and 48% (61/126) were males, and the mean age was 69.90±10.06 years old. Most of patients were diagnosed with multiple myeloma (84%, 53/63) and the remaining ones (16%, 10/63) were diagnosed with smoldering multiple myeloma. According to the ISS classification, 43% (27/63) of patients are in stage III. The data analysis revealed two associations of the studied gene polymorphisms with MG. First, the analysis by gender stratification suggested a decreased predisposition to MG in male carriers of NFKB2 rs12769316 GA and AA genotypes (OR 0.346, 95%CI 0.124–0.965, p=0.043). Second, we observed that patients with BIRC5 rs9904341 CC genotype had a highly significant lower overall survival (recessive model: HR 4.89, 95%CI 5.06 199.70, p<0.01). BIRC5 GGC haplotype (rs4789551, rs9904341, and rs8073069) was found in one patient and absent in controls.
Conclusion
The present study suggests that NFKB2 gene variant (rs12769316, allele A) may be associated with MG susceptibility in males, and BIRC5 (rs9904341) CC genotype may negatively influence MG prognosis. Nonetheless, further studies are needed to validate these findings, enlighten the role of genetic polymorphisms in MG susceptibility and prognosis.
Session topic: 13. Myeloma and other monoclonal gammopathies - Biology
Keyword(s): Survival, Polymorphism, Monoclonal gammopathy, DNA repair
Abstract: PB1938
Type: Publication Only
Background
Monoclonal gammopathies (MG) are a group of disorders characterized by the proliferation of monoclonal plasma cells, which produce and secrete monoclonal immunoglobulin (M protein). Symptomatic multiple myeloma (MM) is characterized by the clonal proliferation of plasma cells. MM is consistently preceded by a pre-neoplastic entity, called monoclonal gammopathy of undetermined significance (MGUS), with an intermediate phase of indolent multiple myeloma (MMI). This disease is a heterogeneous hematological neoplasm characterized by the proliferation of clonal, long-lived plasma cells within the bone marrow (BM) secreting monoclonal proteins and by the presence of so-called CRAB criteria and/or biomarkers of malignancy (as clonal BM plasma cells ³ 60%, involved:uninvolved serum free light chain ratio ³100, >1 focal lesion in MRI studies). Genetic instability and several molecular abnormalities are hallmarks of MM cells. Alterations in DNA repair pathways, namely abnormal activity of non homologous end–joining (NHEJ) repair pathway, are involved in the disease onset and progression. Moreover, it has been observed that virtually all primary MM samples have constitutive nuclear factor-κB (NF-κB) pathway activity, having this pathway a well–established role in MM pathogenesis.
Aims
In this context, we hypothesized that polymorphisms of genes involved in NHEJ repair pathway (XRCC5, XRCC4) and in NF-κB pathway (NFKB2, and BIRC5) may have impact in MG susceptibility and prognosis.
Methods
In the present, a hospital-based case-control study, we analyzed eight polymorphism in four genes (XRCC5, XRCC4, NFKB2, and BIRC5), by genotyping 189 individuals (63 MG patients and 126 controls) using TaqMan qPCR. Results are expressed in terms of frequencies of allele, genotype, haplotype, and genotypic profiles, and their correlation with MG susceptibility. The strength of association between polymorphisms and disease risk was assessed by odds ratio (OR) with 95% confidence interval (CI95%) calculated by logistic regression. We also investigated the association of these SNPs with overall survival through Kaplan Meier curves. All statistical analyses had a significance levels of 95%.
Results
In the patient group, 51% (32/63) of the individuals were females and 49% (31/63) were males; the mean age was 70.11±10.25 years old. Among the control group, 52% (65/126) of the individuals were females and 48% (61/126) were males, and the mean age was 69.90±10.06 years old. Most of patients were diagnosed with multiple myeloma (84%, 53/63) and the remaining ones (16%, 10/63) were diagnosed with smoldering multiple myeloma. According to the ISS classification, 43% (27/63) of patients are in stage III. The data analysis revealed two associations of the studied gene polymorphisms with MG. First, the analysis by gender stratification suggested a decreased predisposition to MG in male carriers of NFKB2 rs12769316 GA and AA genotypes (OR 0.346, 95%CI 0.124–0.965, p=0.043). Second, we observed that patients with BIRC5 rs9904341 CC genotype had a highly significant lower overall survival (recessive model: HR 4.89, 95%CI 5.06 199.70, p<0.01). BIRC5 GGC haplotype (rs4789551, rs9904341, and rs8073069) was found in one patient and absent in controls.
Conclusion
The present study suggests that NFKB2 gene variant (rs12769316, allele A) may be associated with MG susceptibility in males, and BIRC5 (rs9904341) CC genotype may negatively influence MG prognosis. Nonetheless, further studies are needed to validate these findings, enlighten the role of genetic polymorphisms in MG susceptibility and prognosis.
Session topic: 13. Myeloma and other monoclonal gammopathies - Biology
Keyword(s): Survival, Polymorphism, Monoclonal gammopathy, DNA repair