Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma
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Jingmin Shu1, Lihua Li2, Anne E. Sarver2, Emily A. Pope3, Jyotika Varshney2, Venugopal Thayanithy2, Logan Spector1,4, David A. Largaespada1,3,4, Clifford J. Steer1,3,5, Subbaya Subramanian1,2
1Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA
2Department of Surgery, University of Minnesota, Minneapolis, MN, USA
3Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA
4Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
5Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Subbaya Subramanian, e-mail: [email protected]
Keywords: osteosarcoma, 14q32-locus, imprinting, DNA methylation, histone modifications
Received: July 13, 2015 Accepted: November 25, 2015 Published: January 21, 2016
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 imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes.
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