title: Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma.
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 imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes.
authors.affiliation: Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Sarver
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Pope
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jyotika
authors.initials: J
authors.lastname: Varshney
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Thayanithy
authors.affiliation: Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Spector
authors.affiliation: Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA.|Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA.|Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.|Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.affiliation: Masonic Cancer Research Center, University of Minnesota, Minneapolis, MN, USA.|Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D012516:Osteosarcoma / Q000235:genetics / Q000556:secondary*; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor
keywords: 14q32-locus; DNA methylation; histone modifications; imprinting; osteosarcoma