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

ABSTRACT: BACKGROUND: The nuclear factor-?B pathway is an important signaling pathway activated in multiple myeloma cells. Bortezomib inhibits nuclear factor-?B activation and is an important antimyeloma agent. Nevertheless, patients treated with this drug eventually relapse. We hypothesized that the nuclear factor-?B 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-?B family member genes, IKB?, 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-?B family member gene polymorphisms play a role in the development of multiple myeloma and in the response to bortezomib therapy.

SUBMITTER: Du J 

PROVIDER: S-EPMC3084920 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature