体细胞核心和连接蛋白突变的泛癌症图谱。

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-08-28 DOI:10.1038/s41525-023-00367-8
Erin R Bonner, Adam Dawood, Heather Gordish-Dressman, Augustine Eze, Surajit Bhattacharya, Sridevi Yadavilli, Sabine Mueller, Sebastian M Waszak, Javad Nazarian
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引用次数: 1

摘要

最近的基因组数据指出,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,组蛋白基因突变在恶性肿瘤中的患病率及其临床和生物学意义仍不完全明确。为了解决这些知识空白,我们分析了来自儿童、青少年和年轻人(AYA)以及成人癌症患者的12,743个肿瘤中88个连接子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症组蛋白突变图谱。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%)、儿童高级别胶质瘤(pHGG, >60%)和淋巴瘤(>30%)的发生率最高。先前未报道的组蛋白突变在pHGG和其他儿童脑肿瘤中被发现,扩大了与这些癌症相关的组蛋白基因改变的范围。组蛋白突变状态预测包括肾上腺皮质癌在内的肿瘤实体的患者生存结果。反复出现的泛癌组蛋白突变热点被定义并被证明集中在进化上保守的和功能残基上。此外,我们研究了1700种泛癌细胞系的组蛋白基因突变,以验证原发性肿瘤中组蛋白突变的患病率和谱,并衍生出组蛋白相关药物反应谱,揭示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童、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的癌症。
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Pan-cancer atlas of somatic core and linker histone mutations.

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.

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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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