Chang Ti-Cheng, Carter Robert A, Li Yongjin, Li Yuxin, Wang Hong, Edmonson Michael N, Chen Xiang, Arnold Paula, Geiger Terrence L, Wu Gang, Peng Junmin, Dyer Michael, Downing James R, Green Douglas R, Thomas Paul G, Zhang Jinghui
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA.
Genome Med. 2017 Aug 31;9(1):78. doi: 10.1186/s13073-017-0468-3.
Neoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer.
We developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data. Transcriptome sequencing data were incorporated to interrogate the expression status of the neoepitopes.
We present the neoepitope landscape of somatic alterations including missense mutations and oncogenic gene fusions identified in 540 childhood cancer genomes and transcriptomes representing 23 cancer subtypes. We found that 88% of leukemias, 78% of central nervous system tumors, and 90% of solid tumors had at least one predicted neoepitope. Mutation hotspots in KRAS and histone H3 genes encode potential epitopes in multiple patients. Additionally, the ETV6-RUNX1 fusion was found to encode putative neoepitopes in a high proportion (69.6%) of the pediatric leukemia harboring this fusion.
Our study presents a comprehensive repertoire of potential neoepitopes in childhood cancers, and will facilitate the development of immunotherapeutic approaches designed to exploit them. The source code of the workflow is available at GitHub ( https://github.com/zhanglabstjude/neoepitope ).
源自肿瘤特异性体细胞突变的新抗原是儿童癌症免疫治疗的有前景的靶点。然而，由于缺乏对儿童癌症新抗原格局的了解，此类疗法靶向这些表位的潜力仍不确定。迄今为止的研究主要集中在错义突变，而未探索基因融合，而基因融合是儿科癌症中一类主要的致癌驱动因素。
我们开发了一种分析流程，用于使用全基因组测序数据基于体细胞错义突变和基因融合来鉴定推定的新抗原。纳入转录组测序数据以询问新抗原的表达状态。
我们展示了在代表23种癌症亚型的540个儿童癌症基因组和转录组中鉴定出的包括错义突变和致癌基因融合在内的体细胞改变的新抗原格局。我们发现88%的白血病、78%的中枢神经系统肿瘤和90%的实体瘤至少有一个预测的新抗原。KRAS和组蛋白H3基因中的突变热点在多名患者中编码潜在表位。此外，发现ETV6-RUNX1融合在携带这种融合的儿童白血病中高比例（69.6%）编码推定的新抗原。
我们的研究展示了儿童癌症中潜在新抗原的全面清单，并将促进旨在利用它们的免疫治疗方法的开发。该流程的源代码可在GitHub上获取（https://github.com/zhanglabstjude/neoepitope）。
