Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma

Oncotarget
Jingmin ShuSubbaya Subramanian

Abstract

Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that impri...Continue Reading

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Citations

Jul 19, 2017·Expert Review of Respiratory Medicine·Jhon R EnterinaWan L Lam
Oct 20, 2018·Scientific Reports·Idoia Martin-GuerreroAfrica Garcia-Orad
Dec 13, 2018·Cancer Research·Go OshimaNikolai N Khodarev
Apr 29, 2021·Seminars in Cancer Biology·Anup S PathaniaKishore B Challagundla
Jun 3, 2021·Genes·Lilla KrokkerHenriett Butz

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Methods Mentioned

BETA
ChIP
transfection
transfections
biopsy
RNA-Seq
PCR
immunoprecipitation
Assay

Software Mentioned

Partek Genomics Suite
Cufflinks
FastQC
Cuffdiff

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