Digital expression profiling identifies RUNX2, CDC5L, MDM2, RECQL4, and CDK4 as potential predictive biomarkers for neo-adjuvant chemotherapy response in paediatric osteosarcoma.
Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for determining a patients' prognosis is measurement of histopathologic tumor necrosis following pre-operative neo-adjuvant chemotherapy. Unfavourable prognosis is indicated by less than 90% estimated necrosis of the tumor. Neither genetic testing nor molecular biomarkers for diagnosis and prognosis have been described for osteosarcomas. We used the novel nanoString mRNA digital expression analysis system to analyse gene expression in 32 patients with sporadic paediatric osteosarcoma. This system used specific molecular barcodes to quantify expression of a set of 17 genes associated with osteosarcoma tumorigenesis. Five genes, from this panel, which encoded the bone differentiation regulator RUNX2, the cell cycle regulator CDC5L, the TP53 transcriptional inactivator MDM2, the DNA helicase RECQL4, and the cyclin-dependent kinase gene CDK4, were differentially expressed in tumors that responded poorly to neo-adjuvant chemotherapy. Analysis of the signalling relationships of these genes, as well as other expression markers of osteosarcoma, indicated that gene networks linked to RB1, TP53, PI3K, PTEN/Akt, myc and RECQL4 are associated with osteosarcoma. The discovery of these networks provides a basis for further experimental studies of role of the five genes (RUNX2, CDC5L, MDM2, RECQL4, and CDK4) in differential response to chemotherapy.
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Jeffrey W
JW
Martin
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Susan
S
Chilton-MacNeill
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Madhuri
M
Koti
Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Andre J
AJ
van Wijnen
Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada; Departments of Genetics and Pathology, Faculdade de Medicina de Ribeirão Preto - USP, Ribeirão Preto, São Paulo, Brazil.
Jeremy A
JA
Squire
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
Maria
M
Zielenska
D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004358:Drug Therapy / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy / Q000379:methods*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics; D016896:Treatment Outcome
C508357:CDC5L protein, human; D018797:Cell Cycle Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D005819:Genetic Markers; D016601:RNA-Binding Proteins; C493709:RUNX2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C506731:RECQL4 protein, human; D053484:RecQ Helicases