Genome-Informed Targeted Therapy for Osteosarcoma

骨肉瘤 基因组 基因 生物 基因组学 全基因组测序 靶向治疗 遗传学 癌症 计算生物学 癌症研究 生物信息学
作者
Leanne C. Sayles,Marcus R. Breese,Amanda Koehne,Stanley G. Leung,Alex G. Lee,Hengyi Liu,Aviv Spillinger,Avanthi Tayi Shah,Bogdan Tanasă,Krystal Straessler,Florette K. Hazard,Sheri L. Spunt,Neyssa Marina,Grace Kim,Soo‐Jin Cho,Raffi S. Avedian,David G. Mohler,Mi‐Ok Kim,Steven G. DuBois,Douglas S. Hawkins
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:9 (1): 46-63 被引量:363
标识
DOI:10.1158/2159-8290.cd-17-1152
摘要

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.This article is highlighted in the In This Issue feature, p. 1.
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