title: [The clonal evolution of osteosarcomas].
abstract: Osteosarcomas are highly aggressive bone tumors that mainly occur in the metaphyses of long bones in children and adolescents. Genetically, they are characterized by complex structural and numerical aberrations with large intra- and interindividual variations which hamper the identification of the initiating and driving events. Sequencing and copy number analyses in a study of 123 pretherapeutic osteosarcoma samples identified mutations in 14 genes as the potential main drivers. Although almost half of all osteosarcomas could be attributed to mutations in TP53 and RB1, no single driver gene could be found that was clearly responsible for the majority of tumors. There were also no unequivocal correlations between single aberrations and clinicopathological parameters; however, when looking at the mutation signatures, a striking resemblance to BRCA-deficient breast cancer was evident in the majority of osteosarcoma profiles. We therefore focused our interest on genes involved in homologous recombination repair and applied different algorithms that have been shown in the literature to be indicators for functional impairment in these signaling cascades. Indeed, >80 % of osteosarcomas showed signatures similar to BRCA-deficient tumors and in osteosarcoma cell lines a response to poly(ADP-ribose) polymerase (PARP) inhibitors could be demonstrated. Our findings thus imply that multiple oncogenic pathways can converge and lead to chromosomal instability during osteosarcoma evolution resulting in the acquisition of BRCA-like traits, which might be of potential therapeutic relevance.
authors.affiliation: Institut für Pathologie, Knochentumor Referenzzentrum und DOESAK-Referenzregister, Universitätsspital Basel, Schönbeinstrasse 40, 4031, Basel, Schweiz. daniel.baumhoer@usb.ch.
authors.forename: D
authors.initials: D
authors.lastname: Baumhoer
mesh_terms: D000293:Adolescent; D000465:Algorithms; D019313:BRCA1 Protein / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology; D049109:Cell Proliferation; D002648:Child; D060965:Clonal Evolution / Q000235:genetics*; D004252:DNA Mutational Analysis; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D010793:Phthalazines / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C586365:talazoparib
keywords: BRCAness; Homologous recombination; Osteosarcoma; PARP inhibitors; TP53