A group of genetic normal variations in DNA, mainly single nucleotide polymorphisms (SNPs), have been described in association with prevalence, response to treatment, progression-free and overall survival in multiple myeloma (MM). A distinctive and relative 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, associated with progression and prognosis in several malignancies. However, data in MM have not been reported. The aim of this study was to ascertain the prognostic impact of 4 miRSNPs located either in MM related miRNAs target genes or in miRNA biogenesis pathway proteins in MM after autologous-stem cell transplantation (ASCT).
Patients and Methods: One hundred and thirty seven patients with chemosensitive MM (73M/64F, median age 55 years) intensified with ASCT have been studied at our institution. The patients had achieved at least a minimal response after one (117) or two (20) induction regimens prior to ASCT. The median follow-up was 4 years (range 4 months to 16 years). None patient was lost to follow-up. The genes and SNPs evaluated in genomic DNA by allelic discrimination (TaqMan assays) were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667) and XPO5 (rs11077) for miRNA target genes or biogenesis pathway. These genes were selected based on their potential impact on prognosis in solid tumors in previous reports.
In the overall population, the median PFS was 2.8 years (CI 95% 2 to 3.7 years), with a median OS of 9.7 years (CI 95% 5.2 to 14.2 years). OS was significantly longer in patients with SNPs in KRT81 (rs3660; p =0.029) and XPO5 (p =0.012)(Figure). A correlation of SNP in XPO5 with PFS was also observed (p=0.013). This SNP retained its prognostic impact on PFS and OS when a Cox multivariate regression analysis, including age, international staging system and immunoglobulin isotype, was performed (p =0.028 and p =0.014, respectively). When only patients in who the ASCTwas performed after first line treatment were considered, the effect over OS was even deeper (p =0.005; RR 2.9 [IC 95% 1.3 to 6.4]). Furthermore, the effect in OS was also significant in patients achieving CR after ASCT (p =0.03). This SNP was associated to a 17.4% reduction of the related protein, XPO5 (p =NS), on peripheral blood lymphocytes measured by ELISA (USCNK) in healthy donor. There was a trend toward a longer PFS for KRT81 (p =0.17). No other associations with prognosis or toxicities were observed in the remaining SNPs analyzed.
Concerning to the miRNA network, this is the first report in haematological malignancies that a polymorphism in a keratin gene (KRT81), target of diverse miRNA clusters and relevant in the structural cytoplasm framework, has been associated with prognosis. Some of these miRNAs have previously been shown to be altered in MM, and the SNP affects the seed-sequence binding site of these miRNAs. Moreover, a SNP in XPO5 was significantly associated with longer PFS and OS in our study. This gene, exportin 5, mediates pre-miRNA nuclear export. This SNP could modify the miRNA biogenesis pathway through XPO5 protein levels, with a miRNA-target disturbance due to a global impairment of mature miRNAs. Further studies on proliferation and miRNA interaction are encouraged.
Fernández de Larrea:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.
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