title: Impact of MiRSNPs on survival and progression in patients with multiple myeloma undergoing autologous stem cell transplantation.
abstract: OBJECTIVE
  A distinctive new group of polymorphisms is constituted by single-nucleotide polymorphism (SNP) in miRNA processing machinery in miRNA precursor molecules and in miRNA-binding sites, known as miRSNPs. The aim of this study was to ascertain the prognostic impact of six miRSNPs in patients with multiple myeloma and analyze the functional consequences.
  
  
  METHODS
  One hundred and thirty-seven patients with chemosensitive multiple myeloma (73M/64F) intensified with autologous stem cell transplantation (ASCT) were studied. The median follow-up was 4 years. The genes and SNPs evaluated in genomic DNA by allelic discrimination were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667), and MIR196A2 (rs11614913) for miRNA target genes and TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway.
  
  
  RESULTS
  Overall survival (OS) was significantly longer in patients with KRT81 rs3660 C/C variant (P = 0.037). Functional analysis showed that the presence of C variant in KRT81 3' untranslated region (UTR) is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in multiple myeloma cell lines is related to a decreased proliferation. On the other hand, OS was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P = 0.012). There was also a significantly longer progression-free survival (PFS) for this SNP (P = 0.013). This SNP retained its prognostic impact on PFS and OS in a multivariate regression analysis (P = 0.028 and P = 0.014, respectively).
  
  
  CONCLUSIONS
  This is the first report that relates miRSNPs with prognosis in multiple myeloma either in a keratin gene (KRT81), target of diverse miRNA multiple myeloma clusters, or in the miRNA biogenesis pathway-related protein exportin-5.
authors.affiliation: Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Carlos Fernández
authors.initials: CF
authors.lastname: de Larrea
authors.forename: Alfons
authors.initials: A
authors.lastname: Navarro
authors.forename: Rut
authors.initials: R
authors.lastname: Tejero
authors.forename: Natalia
authors.initials: N
authors.lastname: Tovar
authors.forename: Tania
authors.initials: T
authors.lastname: Díaz
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Cibeira
authors.forename: Laura
authors.initials: L
authors.lastname: Rosiñol
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferrer
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rovira
authors.forename: María
authors.initials: M
authors.lastname: Rozman
authors.forename: Mariano
authors.initials: M
authors.lastname: Monzó
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D028884:Karyopherins / Q000235:genetics* / Q000378:metabolism; D053564:Keratins, Hair-Specific / Q000235:genetics* / Q000378:metabolism; D053531:Keratins, Type II / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D014176:Protein Biosynthesis; D017422:Sequence Analysis, DNA; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous
chemical_list: D020413:3' Untranslated Regions; C507600:KRT81 protein, human; D028884:Karyopherins; D053564:Keratins, Hair-Specific; D053531:Keratins, Type II; D035683:MicroRNAs; C446511:XPO5 protein, human