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

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe 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 MethodsIn 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. ResultsSingle 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). ConclusionsNuclear factor-κB family member gene polymorphisms play a role in the development of multiple myeloma and in the response to bortezomib therapy. Polymorphisms of nuclear factor-κB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens

Impact of MiRSNPs on Survival and Progression in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

“…This distinctive and relative new group of polymorphisms is called miRSNPs (8). Although singlenucleotide polymorphism (SNP) in drug metabolic enzymes, DNA repair, or MDR1 have been described in association with prevalence, response to treatment, progression-free (PFS) and overall survival (OS) in multiple myeloma (9,10), no studies have been reported to date with miRSNPs in multiple myeloma. This novel class of SNPs opens a new area of research in cancer biology and clinical oncology.…”

Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk

“…In addition, the A allele of the rs11160707 SNP was associated with better progression-free survival [233], and the authors suggested that this polymorphism may correlate with disrupted TRAF3 activation. Hence, the indicated polymorphisms may be promising for oncogenomic studies.…”

“…The only study analyzing the association of TRAF3 SNPs with cancer risk was conducted by Du et al [233], who reported that the A allele of the rs7143468 polymorphism is related to higher multiple myeloma (MM) risk, whereas the A allele of the rs12147254 polymorphism, conversely, correlates with lower MM risk. In addition, the A allele of the rs11160707 SNP was associated with better progression-free survival [233], and the authors suggested that this polymorphism may correlate with disrupted TRAF3 activation.…”

Genetics and molecular epidemiology of multiple myeloma: The rationale for the IMMEnSE consortium (Review)

“…An association between the carriers of the G allele for the -8C/G SNP in the 20S proteasome subunit coding gene PSMA6 and a better 5-year OS has been also shown (135). Recently, Du et al evidenced the association of the carriers of the A allele of the TRAF3 SNP rs11160707 with an improved PFS, while the variant alleles for two NFKB2 SNPs (rs12769316 and rs1056890) were associated, respectively, with an increased and a decreased OS (93).…”

“…The activation of the nuclear transcription factor NF-κB is thought to be one of the most important factors to enhance cell proliferation in MM pathogenesis (89,90). The minor alleles of SNPs in genes related to the NF-κB pathway, such as the inhibitor IκBα (rs2233406, rs3138054, rs2233419) and the transcriptional activator TRAF3 (rs12147254) have been associated with a protective effect on MM development (91)(92)(93). Several polymorphisms in genes related to insulin metabolism resulted associated with MM risk.…”