title: 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.
  
  
  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.affiliation: Department of Hematology, The Myeloma & Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Jun
authors.initials: J
authors.lastname: Huo
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Chunyang
authors.initials: C
authors.lastname: Zhang
authors.forename: Weijun
authors.initials: W
authors.lastname: Fu
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D015999:Multivariate Analysis; D052003:NF-kappa B p52 Subunit / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011719:Pyrazines / Q000008:administration & dosage; D018570:Risk Assessment; D012307:Risk Factors; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D020672:I-kappa B Proteins; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; D011719:Pyrazines; D048008:TNF Receptor-Associated Factor 3; D000069286:Bortezomib