IMPACT OF MIRSNPS ON SURVIVAL AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA UNDERGOING AUTOLOGOUS STEM CELL TRANSPLANTATION Running title: MiRSNPs in myeloma

Purpose: A distinctive new group of polymorphisms is constituted by SNPs in microRNAs (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 6 miRSNPs in multiple myeloma (MM) patients and analyze the functional consequences. Experimental design: One hundred and thirty seven patients with chemosensitive MM (73M/64F) intensified with 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), 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’UTR region is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in MM 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). Conclusion: This is the first report that relates miRSNPs with prognosis in MM either in a keratin gene (KRT81), target of diverse miRNA MM clusters, or in the miRNA biogenesis pathway related protein exportin-5. Research. on April 13, 2017. © 2012 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on April 26, 2012; DOI: 10.1158/1078-0432.CCR-12-0191