最近的基因组数据表明，体细胞突变在癌症中改变核心组蛋白和连接组蛋白编码基因的作用越来越重要。然而，组蛋白基因突变在恶性肿瘤中的患病率以及临床和生物学意义尚未完全确定。为了填补这些知识空白，我们对来自儿童、青少年和成人癌症患者的12,743个肿瘤进行了分析，涉及88个连接组蛋白和核心组蛋白基因的体细胞突变。我们建立了一个针对患者年龄、生存预后和肿瘤部位进行定位的全癌组蛋白突变图谱。总体而言，11%的肿瘤携带了体细胞组蛋白突变，其中软骨肉瘤（67%）、儿童高级别胶质瘤（pHGG，>60%）和淋巴瘤（>30%）的患病率最高。在pHGG和其他儿童脑肿瘤中发现了之前未报告的组蛋白突变，扩展了与这些癌症相关的组蛋白基因变异的谱系。组蛋白突变状态预测了肿瘤实体中患者生存预后，包括肾上腺皮质癌。我们确定了经常发生的全癌组蛋白突变热点，并显示其汇聚在保守进化的功能残基上。此外，我们研究了1700种全癌细胞系中的组蛋白基因突变，以验证在原发性肿瘤中观察到的组蛋白突变的患病率和谱系，并推导出与组蛋白突变癌细胞相关的药物反应谱系，揭示了针对组蛋白突变癌细胞的候选药物。本研究首次以儿童、青少年和成人癌症为背景，提供了包括核心组蛋白和连接组蛋白突变在内的图谱，为在组蛋白和染色质变化的背景下重新定义特定癌症提供了框架。©2023. Springer Nature Limited和沙特阿布杜拉齐兹大学基因医学研究卓越中心。

Recent genomic data points to a growing role for somatic mutations altering core histone and linker histone-encoding genes in cancer. However, the prevalence and the clinical and biological implications of histone gene mutations in malignant tumors remain incompletely defined. To address these knowledge gaps, we analyzed somatic mutations in 88 linker and core histone genes across 12,743 tumors from pediatric, adolescent and young adult (AYA), and adult cancer patients. We established a pan-cancer histone mutation atlas contextualized by patient age, survival outcome, and tumor location. Overall, 11% of tumors harbored somatic histone mutations, with the highest rates observed among chondrosarcoma (67%), pediatric high-grade glioma (pHGG, >60%), and lymphoma (>30%). Previously unreported histone mutations were discovered in pHGG and other pediatric brain tumors, extending the spectrum of histone gene alterations associated with these cancers. Histone mutation status predicted patient survival outcome in tumor entities including adrenocortical carcinoma. Recurrent pan-cancer histone mutation hotspots were defined and shown to converge on evolutionarily conserved and functional residues. Moreover, we studied histone gene mutations in 1700 pan-cancer cell lines to validate the prevalence and spectrum of histone mutations seen in primary tumors and derived histone-associated drug response profiles, revealing candidate drugs targeting histone mutant cancer cells. This study presents the first-of-its-kind atlas of both core and linker histone mutations across pediatric, AYA, and adult cancers, providing a framework by which specific cancers may be redefined in the context of histone and chromatin alterations.© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.