Abstract
Abstract PURPOSE: Sensitivity of preoperative chemotherapy, evaluated by a histological analysis using resected tumor tissue, is the most important prognostic factor for osteosarcoma (OS). Methotrexate, doxorubicin, cisplatin (MAP regimen), and ifosfamide (IFO) are recognized as key drugs for OS, although it is still debatable whether addition of IFO for all OS patient is beneficial or not. In this study, to construct a prediction system of chemosensitivity of preoperative chemotherapy for pediatric OS patients, array CGH and NGS technologies were applied. METHODS: Pre-therapeutic biopsy tumor samples of 30 pediatric conventional OS patients treated in our institute who had homogeneous clinicopathological- and therapeutic- background were analyzed. The patients were divided into three groups (A:MAP-sensitive, B:IFO-sensitive and C:resistant to both) according to the histological response to chemotherapy including MAP and/or IFO. Twenty-two tumor samples were used as a learning set for searching candidate markers. Additionally, 8 tumor samples were used for independent analysis as a validation set. Genomic DNAs were prepared from frozen biopsy samples and used for CGH analysis with Agilent 44k DNA microarray. Target-sequencing by using the Ion Torrent AmpliSeq Comprehensive Cancer Panel containing 409 cancer-related genes were also conducted for 10 tumor/non-tumor pairs. RESULTS: Survival analysis of this cohort assured that response levels to chemotherapy were significantly correlated to the patient outcomes. Differential aberration analyses of the copy number data resulted in selection of 8 putative genomic markers for classifying into A, B and C groups with differential chemosensitivity. Scoring system to predict chemosensitivity of each tumor was developed with these genomic markers and subsequent validation analysis indicated that the scoring system was remarkably consistent to the patient properties. Target re-sequencing of 409 cancer-related genes by using Ion Proton sequencer identified 98 candidate non-synonymous single nucleotide variations (SNVs) (average 10 SNVs per tumor), however, significantly recurrent mutations in C group have not been observed so far. CONCLUSION: Our results indicated that copy number changes in OS biopsy samples could be good predictors of response to preoperative chemotherapy. These signatures as well as global mutation information may be useful for the future genomics-based personalized chemotherapy for OS patients. Citation Format: Shintaro Iwata, Tsukasa Yonemoto, Hajime Kageyama, Hiroto Kamoda, Sana Yokoi, Hiroki Nagase, Akira Nakagawara, Takeshi Ishii, Miki Ohira. Genomic alterations in biopsy samples predict the chemosensitivity of pediatric osteosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3102. doi:10.1158/1538-7445.AM2014-3102
Published Version
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