Polymorphisms of nuclear factor-κB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens

• Published in: Haematologica (Roma) Vol. 96; no. 5; pp. 729 - 737
• Main Authors: Du, Juan, Huo, Jun, Shi, Jun, Yuan, Zhengang, Zhang, Chunyang, Fu, Weijun, Jiang, Hua, Yi, Qing, Hou, Jian
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.05.2011
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Base Sequence; Biological and medical sciences; Boronic Acids - administration & dosage; Bortezomib; Female; Gene Frequency; Genetic Predisposition to Disease - genetics; Genotype; Haplotypes; Hematologic and hematopoietic diseases; Humans; I-kappa B Proteins - genetics; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Kaplan-Meier Estimate; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multivariate Analysis; NF-kappa B p52 Subunit - genetics; Original; Polymorphism, Single Nucleotide; Pyrazines - administration & dosage; Risk Assessment; Risk Factors; TNF Receptor-Associated Factor 3 - genetics; Treatment Outcome; Antineoplastic agent; Human; Immunopathology; multiple myeloma; Bortezomib; Prognosis; Genetic variability; Hematology; Genotype; Malignant hemopathy; Myeloma; NF-κB; Treatment; Immunoglobulinopathy; SNP; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Dipeptides; Multigene family; Transcription factor NFκB; Therapeutic protocol; Cancer; Polymorphism
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2010.030577

The nuclear factor-κB pathway is an important signaling pathway activated in multiple myeloma cells. Bortezomib inhibits nuclear factor-κB activation and is an important antimyeloma agent. Nevertheless, patients treated with this drug eventually relapse. We hypothesized that the nuclear factor-κB pathway may be associated with multiple myeloma and patients' responses to bortezomib. In this study we analyzed 26 polymorphism sites of nuclear factor-κB family member genes, IKBα, NFKB2, and TRAF3, in 527 unrelated Chinese Han subjects (252 with multiple myeloma and 275 controls) using a Sequenom MassARRAY genotyping assay, and examined the outcome of 83 patients treated with a bortezomib-based regimen. Single nucleotide polymorphisms in the TRAF3 rs12147254 A allele and a specific haplotype 1 of TRAF3 [GAACAG] are associated with a decreased risk of multiple myeloma (odds ratio 0.709, P<0.001, and odds ratio 0.543, P<0.0001), while TRAF3 haplotype 4 [GGACAG] was associated with an increased risk of development of multiple myeloma (odds ratio 2.099, P=0.001). Moreover, the TRAF3 rs11160707 GA+AA genotype was significantly associated with a better progression-free survival (P=0.018). Patients with the NFKB2 rs12769316 GA+AA genotype had a superior overall survival (P=0.020), while those with the rs1056890 CT+TT genotype had an inferior overall survival (P=0.037). In an exploratory analysis, patients with the GA+AA/CC/GG genotype at the rs12769316, rs1056890, and rs11160707 sites had a significantly superior overall survival compared to patients with a wild-type genotype (P=0.007). In the multivariable analysis, TRAF3 rs11160707 was found to be an independent favorable factor for progression-free survival (hazard ratio 0.428, P=0.028). Nuclear factor-κB family member gene polymorphisms play a role in the development of multiple myeloma and in the response to bortezomib therapy.