Abstract 1281: Genomic structure variation in large screening for pediatric sarcoma therapy

Abstract

Abstract Complex chromosomal aberrations such as amplification and deletion of DNA copy number are frequently seen in sarcoma. Fifty-five DNA structure variation has been listed as standard clinical diagnosis for sarcoma by standard of National Comprehensive Cancer Network (NCCN). However, copy number variation (CNV) as a biomarker of drug treatment for pediatrics sarcoma is still unclear, especially for relapsed and high recurrent patients of pediatric sarcoma. The paper aims to detect the prognosis biomarkers for rhabdomyosarcoma, Ewing's sarcoma (ES), and osteosarcoma based on copy number variation for 128 FDA-approved cancer drugs systematically. The 182 copy number variation (CNV) profiles from clinical sarcoma patients across three types of sarcoma, including osteosarcoma, rhabdomyosarcoma and ES, are observed. Cox survival regression model is used to select significant cancer-related CNVs systematically by correlation with overall survival analysis. 532 significant common CNVs and 782 specific CNVs for different types of sarcoma are observed by p-value <0.01. By comparing with healthy persons, COSMIC database, 947 cancer cells and our INHOUSE tumor datasets, 32 out of 532 CNVs for specific sarcoma types are validated. This systematic CNV comparison makes it possible to map DNA copy number changes and identify chromosomal regions containing “target genes” responsible for tumor development and/or progression. Integrating large-scale drug screening with copy number variation analysis on 38 sarcoma cancer cells, 95 out of 532 are confirmed as drugs resistance and sensitive biomarkers for different types of sarcoma. 15 chemotherapies show strong signals connecting with 42 biomarkers, including genes MYC, RAD21, and RB1 amplification. By bridging molecular biomarkers between tumors and sarcoma cell lines, 5 optimum drugs associated with 14 enzyme biomarkers are recommended for pediatric rhabdomyosarcoma, ES, and osteosarcoma treatment respectively. The research not only detects copy number variations both of sarcoma cell lines and tumors, but also provides novel insights into drug biomarkers based on copy number amplification or deletion for bone sarcoma and soft tissue sarcoma, respectively. Citation Format: Lijun Cheng, Pooja Chandra, Limei Wang, Karen Pollok, Pankita Pandya, Mary Murray, Jacquelyn Carter, Michael Ferguson, Mohammad Reza, Mashall Mark, Lang Li, Jamie Renbarger. Genomic structure variation in large screening for pediatric sarcoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1281.