Secondary Radiation-Induced Bone Tumours Demonstrate a High Degree of Genomic Instability Predictive of a Poor Prognosis

Christine      Rumenapp; Jan      Smida; Iria      Gonzalez-Vasconcellos; Daniel      Baumhoer; Bernard      Malfoy; Nabila-Sandra      Hadj-Hamou; Bahar      Sanli-Bonazzi; Michaela      Nathrath; Michael      J. Atkinson; Michael      Rosemann

doi:10.2174/138920212802510420

Abstract

Secondary bone tumours arising in the field of a preceding radiotherapy are a serious late effect, in particular considering the increasing survival times in patients treated for paediatric malignancies. In general, therapy associated tumours are known to show a more aggressive behaviour and a limited response to chemotherapy compared with their primary counterparts. It is not clear however whether this less favourable outcome is caused by inherent genetic factors of the tumour cells or by a general systemic condition of the patient. To elucidate this we analysed a series of bone sarcomas with a history of prior irradiation for the presence of genomic alterations and compared them with the alterations identified earlier in primary osteosarcomas. We analysed seven radiation induced bone sarcomas for genome-wide losses of heterozygosity (LOH) using Affymetrix 10K2 high-density single nucleotide polymorphism (SNP) arrays. Additionally, copy number changes were analysed at two distinct loci on 10q that were recently found to be of major prognostic significance in primary osteosarcomas. All the investigated tumours showed a LOH at 10q21.1 with 86% of cases (6/7) revealing a total genome-wide LOH score above 2400 and more than 24% of the genome being affected. Our results indicate similar genetic alterations in radiation induced sarcomas of bone and primary osteosarcomas with a poor prognosis. We speculate that the high degree of genomic instability found in these tumours causes the poor prognosis irrespective of the initiating event.

Keywords: Genomic instability, Loss-of-heterozygosity, Osteosarcom, Predictive assay, Radiation-induced, SNP-array, Therapy-related, Therapy response, heterozygosity, radiotherapy , induced bone sarcomas