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.

最近的基因组数据表明，体细胞突变改变核心组蛋白和连接组蛋白编码基因在癌症中的作用越来越大。然而，恶性肿瘤中组蛋白基因突变的患病率及其临床和生物学意义仍未完全确定。为了解决这些知识差距，我们分析了来自儿科、青少年和年轻人 (AYA) 以及成年癌症患者的 12,743 个肿瘤中 88 个接头和核心组蛋白基因的体细胞突变。我们根据患者年龄、生存结果和肿瘤位置建立了泛癌组蛋白突变图谱。总体而言，11% 的肿瘤存在体细胞组蛋白突变，其中软骨肉瘤 (67%)、儿童高级别神经胶质瘤 (pHGG，>60%) 和淋巴瘤 (>30%) 中观察到的比率最高。在 pHGG 和其他儿童脑肿瘤中发现了以前未报道的组蛋白突变，扩大了与这些癌症相关的组蛋白基因改变的范围。组蛋白突变状态可预测包括肾上腺皮质癌在内的肿瘤实体的患者生存结果。复发性泛癌组蛋白突变热点被定义并显示出集中在进化保守和功能残基上。此外，我们研究了 1700 个泛癌细胞系中的组蛋白基因突变，以验证原发性肿瘤中组蛋白突变的流行率和谱，并得出组蛋白相关药物反应谱，揭示了针对组蛋白突变癌细胞的候选药物。这项研究首次展示了儿科、AYA 和成人癌症的核心和连接组蛋白突变图谱，提供了一个框架，通过该框架可以在组蛋白和染色质改变的背景下重新定义特定癌症。