Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
Haematologica. 2011 May;96(5):729-37. doi: 10.3324/haematol.2010.030577. Epub 2011 Jan 12.
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.
核因子-κB 通路是多发性骨髓瘤细胞中被激活的重要信号通路。硼替佐米抑制核因子-κB 的激活，是一种重要的抗骨髓瘤药物。然而，接受这种药物治疗的患者最终还是会复发。我们假设核因子-κB 通路可能与多发性骨髓瘤和患者对硼替佐米的反应有关。
在这项研究中，我们使用Sequenom MassARRAY 基因分型检测方法，分析了 527 名无血缘关系的汉族个体（252 名多发性骨髓瘤患者和 275 名对照者）中核因子-κB 家族成员基因 IKBα、NFKB2 和 TRAF3 的 26 个单核苷酸多态性位点，并检测了 83 名接受硼替佐米治疗方案的患者的结果。
TRAF3 rs12147254 A 等位基因和 TRAF3 [GAACAG]特定单倍型 1 的单核苷酸多态性与多发性骨髓瘤的发病风险降低相关（比值比 0.709，P<0.001 和比值比 0.543，P<0.0001），而 TRAF3 单倍型 4 [GGACAG]与多发性骨髓瘤的发病风险增加相关（比值比 2.099，P=0.001）。此外，TRAF3 rs11160707 GA+AA 基因型与无进展生存期显著相关（P=0.018）。NFKB2 rs12769316 GA+AA 基因型的患者总生存率较好（P=0.020），而 rs1056890 CT+TT 基因型的患者总生存率较差（P=0.037）。在一项探索性分析中，rs12769316、rs1056890 和 rs11160707 位点 GA+AA/CC/GG 基因型的患者总生存率明显优于野生型基因型的患者（P=0.007）。多变量分析发现，TRAF3 rs11160707 是无进展生存期的独立有利因素（风险比 0.428，P=0.028）。
核因子-κB 家族成员基因多态性在多发性骨髓瘤的发生发展以及硼替佐米治疗反应中起作用。
