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

Abstract

BACKGROUND:

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.

DESIGN AND METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

Nuclear factor-κB family member gene polymorphisms play a role in the development of multiple myeloma and in the response to bortezomib therapy.

• Authors: Juan Du, Jun Huo, Jun Shi, Zhengang Yuan, Chunyang Zhang, Weijun Fu, Hua Jiang, Qing Yi, Jian Hou
• Journal: Haematologica (Haematologica) Vol. 96 Issue 5 Pg. 729-37 (May 2011) ISSN: 1592-8721 [Electronic] Italy
• PMID: 21228035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• I-kappa B Proteins
• NF-kappa B p52 Subunit
• NFKB2 protein, human
• Pyrazines
• TNF Receptor-Associated Factor 3
• Bortezomib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Base Sequence
• Boronic Acids (administration & dosage)
• Bortezomib
• Female
• Gene Frequency
• Genetic Predisposition to Disease (genetics)
• Genotype
• Haplotypes
• Humans
• I-kappa B Proteins (genetics)
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Multiple Myeloma (drug therapy, genetics)
• Multivariate Analysis
• NF-kappa B p52 Subunit (genetics)
• Polymorphism, Single Nucleotide
• Pyrazines (administration & dosage)
• Risk Assessment
• Risk Factors
• TNF Receptor-Associated Factor 3 (genetics)
• Treatment Outcome