Abstract 3421: Serial whole exome sequencing showed the genetic aggravation of refractory osteosarcoma

Abstract

Abstract Osteosarcoma is the most common malignant bone tumor in children and adolescents with frequent lung metastasis. As the survival has not been improved with chemotherapy for the last two decades, novel therapeutic approaches are required to efficiently treat osteosarcoma. Genomic analyses have revealed biologically useful information and genetically altered therapeutic targets. The subject of this study was a 25 year old patient with conventional high-grade osteosarcoma with multiple metastasis of lung, lymph nodes and chest wall, who had failed from several palliative systemic chemotherapies and radiotherapy. We performed whole exome sequencing of the gDNA from peripheral blood mononucleated cells (PBMC) and formalin fixed paraffin embedded (FFPE) tissues of primary tumor, secondary (recurrence 1) and tertiary (recurrence 2) metastatic tumors. Samples were sequenced using one lane of paired-end, 100 bp reads on Illumina Hiseq for each sample. Here, we present an analysis result using VarScan and custom-made programs for the detection of somatic mutations and loss of heterozygosity (LOHs) in exome data from changes of genetic variations throughout the disease progression compared to blood germ-line sequencing data. As a result, we observed the 36 common somatic mutated genes, including p73 and TSHR, in three tumor types. And we indentified the somatic mutations affecting the functions of known cancer genes, RBM15, SYNE1, GNAQ and XPA, which were only present in the secondary and/or tertiary metastatic tumors but not in the primary tumor. Especially, GNAQ mutations which is found in the metastatic tumors, is known to be mutated in 50% of melanoma and driven constitutive activity of the MAPK pathway. Therefore, GNAQ mutation in recurrent osteosarcoma patient might be a potential marker for new therapeutic strategies of inhibiting MAPK pathway. In conclusion, the ability to track clonal evolution in cancers may provide new strategies and opportunities for drug development, especially in refractory and rare diseases. Citation Format: Su Jin Heo, Ji Woong Kim, Woo Sun Kwon, Hyo Ki Kim, Min Hee Hong, Woo Ick Yang, Se-Kyu Kim, Hyo Song Kim, Hyun Cheol Chung, Tae Hyun Hwang, Sun Young Rha. Serial whole exome sequencing showed the genetic aggravation of refractory 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 3421. doi:10.1158/1538-7445.AM2014-3421