title: An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification.
abstract: IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the combination of 2 independent molecular genetic events is related to synergistic increases in sIL-6r levels. We also show that the rs2228145 minor allele is related to increased expression levels of an IL-6r splice variant that purportedly codes exclusively for a sIL-6r isoform. Together, the SNP rs2228145 minor allele C and amplification of chromosome 1q21 are significantly correlated to an increase in sIL-6r levels, which are associated with lower overall survival in 70-gene low-risk disease, and aid in identification of the intermediate-risk MM group.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Owen W
authors.initials: OW
authors.lastname: Stephens
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pingping
authors.initials: P
authors.lastname: Qu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shweta
authors.initials: S
authors.lastname: Chavan
authors.forename: Erming
authors.initials: E
authors.lastname: Tian
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
mesh_terms: D017398:Alternative Splicing; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D009101:Multiple Myeloma / Q000097:blood* / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000097:blood* / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D019947:Receptors, Interleukin-6; D004247:DNA
references.citation: Hum Mutat. 2003 Apr;21(4):450-1
references.pmid: 12655571
references.citation: Blood. 1993 Jun 15;81(12):3357-64
references.pmid: 8507873
references.citation: Eur J Biochem. 2000 May;267(9):2624-31
references.pmid: 10785383
references.citation: J Biol Chem. 2011 Apr 29;286(17):14804-11
references.pmid: 21454673
references.citation: Am J Hum Genet. 2007 Apr;80(4):716-26
references.pmid: 17357077
references.citation: Blood. 2002 Mar 1;99(5):1745-57
references.pmid: 11861292
references.citation: Blood. 2006 Sep 15;108(6):2020-8
references.pmid: 16728703
references.citation: Genes Chromosomes Cancer. 2007 Aug;46(8):717-23
references.pmid: 17444494
references.citation: J Immunol. 1994 May 15;152(10):4958-68
references.pmid: 8176214
references.citation: Leukemia. 2009 Nov;23(11):1941-56
references.pmid: 19657360
references.citation: Eur J Immunol. 1994 Aug;24(8):1945-8
references.pmid: 8056053
references.citation: Blood. 1994 Nov 1;84(9):3063-70
references.pmid: 7949178
references.citation: Exp Hematol. 1998 Jul;26(7):597-603
references.pmid: 9657134
references.citation: PLoS Genet. 2007 Jun;3(6):e99
references.pmid: 17571926
references.citation: J Child Neurol. 2011 Jan;26(1):113-6
references.pmid: 21212457
references.citation: FASEB J. 2001 Jan;15(1):43-58
references.pmid: 11149892
references.citation: Br J Haematol. 1996 May;93(2):398-400
references.pmid: 8639436
references.citation: J Immunol. 2004 May 1;172(9):5676-83
references.pmid: 15100312
references.citation: Genes Immun. 2004 Sep;5(6):513-6
references.pmid: 15306846
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924-8
references.pmid: 8265649
references.citation: Oncogene. 2005 Apr 7;24(15):2461-73
references.pmid: 15735737
references.citation: Blood. 1995 Feb 15;85(4):863-72
references.pmid: 7849308
references.citation: Nat Genet. 2008 Dec;40(12):1466-71
references.pmid: 19029900
references.citation: Mayo Clin Proc. 1994 Sep;69(9):895-902
references.pmid: 8065197
references.citation: Annu Rev Immunol. 2005;23:1-21
references.pmid: 15771564
references.citation: FEBS Lett. 1989 Jul 3;250(2):607-10
references.pmid: 2787758
references.citation: Cytokine. 1992 Mar;4(2):96-100
references.pmid: 1633265
references.citation: Cancer Res. 2004 Mar 15;64(6):2016-23
references.pmid: 15026338
references.citation: Eur J Immunol. 1993 Apr;23(4):820-4
references.pmid: 8458373
references.citation: J Biol Chem. 2003 Jun 20;278(25):22331-40
references.pmid: 12682046
references.citation: Blood. 2007 Mar 15;109(6):2276-84
references.pmid: 17105813
references.citation: Clin Cancer Res. 1999 Oct;5(10):2693-7
references.pmid: 10537331
references.citation: Clin Lung Cancer. 2006 Jan;7(4):273-5
references.pmid: 16512982
references.citation: Cancer Cell. 2011 Apr 12;19(4):456-69
references.pmid: 21481788
references.citation: Leuk Res. 2009 Nov;33(11):1570-3
references.pmid: 19406470
references.citation: Blood. 2006 Sep 1;108(5):1724-32
references.pmid: 16705089
references.citation: Nature. 1988 Mar 3;332(6159):83-5
references.pmid: 3258060