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  • genomic vulnerability to line-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma

    جزئیات بیشتر مقاله
    • تاریخ ارائه: 1392/07/24
    • تاریخ انتشار در تی پی بین: 1392/07/24
    • تعداد بازدید: 1218
    • تعداد پرسش و پاسخ ها: 0
    • شماره تماس دبیرخانه رویداد: -
    background: the aim of this study was to clarify the role of global hypomethylation of repetitive elements indetermining the genetic and clinical features of multiple myeloma (mm). methods: we assessed global methylation levels using four repetitive elements (long interspersed nuclearelement-1 (line-1), alu ya5, alu yb8, and satellite-α) in clinical samples comprising 74 mm samples and 11 benigncontrol samples (7 cases of monoclonal gammopathy of undetermined significance (mgus) and 4 samples ofnormal plasma cells (npc)). we also evaluated copy-number alterations using array-based comparative genomichybridization, and performed methyl-cpg binding domain sequencing (mbd-seq). results: global levels of the repetitive-element methylation declined with the degree of malignancy of plasmacells (npc>mgus>mm), and there was a significant inverse correlation between the degree of genomic loss andthe line-1 methylation levels. we identified 80 genomic loci as common breakpoints (cbps) around commonly lostregions, which were significantly associated with increased line-1 densities. mbd-seq analysis revealed that averagedna-methylation levels at the cbp loci and relative methylation levels in regions with higher line-1 densities alsodeclined during the development of mm. we confirmed that levels of methylation of the 5’ untranslated region ofrespective line-1 loci correlated strongly with global line-1 methylation levels. finally, there was a significantassociation between line-1 hypomethylation and poorer overall survival (hazard ratio 2.8, p = 0.015). conclusion: global hypomethylation of line-1 is associated with the progression of and poorer prognosis for mm,possibly due to frequent copy-number loss.

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