Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
Clin Cancer Res. 2012 Jul 1;18(13):3697-704. doi: 10.1158/1078-0432.CCR-12-0191. Epub 2012 Apr 26.
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.
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.
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).
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.
一组独特的新多态性由 miRNA 前体分子中的 miRNA 加工机制中的单核苷酸多态性（SNP）和 miRNA 结合位点中的 SNP 组成，称为 miRSNPs。本研究旨在确定多发性骨髓瘤患者中六个 miRSNPs 的预后影响，并分析其功能后果。
研究了 137 名接受化学敏感多发性骨髓瘤（73M/64F）强化自体干细胞移植（ASCT）的患者。中位随访时间为 4 年。通过等位基因鉴别法在基因组 DNA 中评估的基因和 SNP 是 miRNA 靶基因的 KRT81（rs3660）、AFF1（rs17703261）、FAM179b（rs1053667）和 MIR196A2（rs11614913）以及 miRNA 生物发生途径的 TRBP（rs784567）和 XPO5（rs11077）。
KRT81 rs3660 C/C 变体患者的总生存期（OS）显著延长（P=0.037）。功能分析表明，KRT81 3'UTR 中 C 变体的存在与蛋白水平降低有关。此外，在多发性骨髓瘤细胞系中用 siRNA 降低 KRT81 蛋白水平与增殖减少有关。另一方面，XPO5 rs11077 的 C/C 或 A/C 变体患者的 OS 显著延长（P=0.012）。该 SNP 的无进展生存期（PFS）也显著延长（P=0.013）。在多变量回归分析中，该 SNP 对 PFS 和 OS 仍具有预后影响（P=0.028 和 P=0.014）。
这是第一个报道 miRNA 多态性与多发性骨髓瘤的预后相关的报告，无论是在角蛋白基因（KRT81），还是在 miRNA 簇的多种 miRNA 靶基因，还是在 miRNA 生物发生途径相关的蛋白输出蛋白-5 中。
