title: Recurrent RECQL4 imbalance and increased gene expression levels are associated with structural chromosomal instability in sporadic osteosarcoma.
abstract: Osteosarcoma (OS) is an aggressive bone tumor with complex abnormal karyotypes and a highly unstable genome, exhibiting both numerical- and structural-chromosomal instability (N- and S-CIN). Chromosomal rearrangements and genomic imbalances affecting 8q24 are frequent in OS. RECQL4 gene maps to this cytoband and encodes a putative helicase involved in the fidelity of DNA replication and repair. This protective genomic function of the protein is relevant because often patients with Rothmund-Thomson syndrome have constitutional mutations of RECQL4 and carry a very high risk of developing OS. To determine the relative level of expression of RECQL4 in OS, 18 sporadic tumors were studied by reverse transcription-polymerase chain reaction. All tumors overexpressed RECQL4 in comparison to control osteoblasts, and fluorescence in situ hybridization analysis of tumor DNA showed that expression levels were strongly copy number-dependent. Relative N- and S-CIN levels were determined by classifying copy number transitions within array comparative genomic hybridization profiles and by enumerating the frequency of break-apart fluorescence in situ hybridization within 8q24 using region-specific and control probes. Although there was no evidence that disruption of 8q24 in OS led to an elevated expression of RECQL4, there was a marked association between increased overall levels of S-CIN, determined by copy number transition frequency and higher levels of RECQL4.
authors.affiliation: Department of Pathology and Molecular Medicine, Richardson Labs, Queen's University, Kingston, Ontario, Canada.
authors.forename: Georges
authors.initials: G
authors.lastname: Maire
authors.forename: Maisa
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Susan
authors.initials: S
authors.lastname: Chilton-MacNeill
authors.forename: Paul S
authors.initials: PS
authors.lastname: Thorner
authors.forename: Maria
authors.initials: M
authors.lastname: Zielenska
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000235:genetics*; D002648:Child; D043171:Chromosomal Instability / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D012516:Osteosarcoma / Q000235:genetics*; D053484:RecQ Helicases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C506731:RECQL4 protein, human; D053484:RecQ Helicases