Yang Xiaodi, Wang Qian, Sun Yuhua, Zhang Ziding, Wuchty Stefan, Liang Zeyin, Dong Yujun
Department of Hematology, Peking University First Hospital, Beijing, China.
College of Biological Sciences, China Agricultural University, Beijing, China.
Commun Biol. 2024 Dec 6;7(1):1630. doi: 10.1038/s42003-024-07293-0.
Hematologic malignancies cause significant morbidity/mortality in both children and young adults (CYAs) as well as older adults (OAs). Yet their biological underpinnings remain inadequately understood. Here, we analyzed clinical and genomic disparities between CYAs and OAs in various hematologic malignancies. We found substantial differences in clinical features such as patient sex, ethnicity, metastasis rates, and tumor subtypes. Genomically, most CYA hematologic malignancies indicated lower mutational burden. Subsequently, we identified differentially mutated genes (DMGs) with varying mutation rates between CYAs and OAs, noting fewer mutations in CYAs for most genes such as TP53, TET2, and DNMT3A. In contrast, several DMGs (i.e., NRAS, KRAS, SMARCA4, ID3, PTPN11, WT1, and KIT) were overrepresented in CYAs. We further investigated human protein interacting partners of these identified DMGs that were highly mutated in CYAs/OAs, respectively, and found significant differences in network topological and functional roles. Notably, CYA malignancies demonstrated extensive copy number alterations (CNAs) and more driver gene fusions. In particular, four CNA differential genes (i.e., ARID1B, MYB, TP53, and ESR1) were overrepresented as amplifications and deletions in CYAs and OAs, respectively. Ultimately, we demonstrated a landscape comparative view of clinically actionable genetic events in CYAs and OAs, providing clues for age-related personalized treatment.
血液系统恶性肿瘤在儿童和青年（CYA）以及老年人（OA）中均会导致显著的发病率和死亡率。然而，它们的生物学基础仍未得到充分了解。在此，我们分析了各类血液系统恶性肿瘤中CYA和OA之间的临床和基因组差异。我们发现患者性别、种族、转移率和肿瘤亚型等临床特征存在显著差异。在基因组方面，大多数CYA血液系统恶性肿瘤显示出较低的突变负担。随后，我们鉴定出CYA和OA之间具有不同突变率的差异突变基因（DMG），注意到对于大多数基因，如TP53、TET2和DNMT3A，CYA中的突变较少。相比之下，一些DMG（即NRAS、KRAS、SMARCA4、ID3、PTPN11、WT1和KIT）在CYA中过度表达。我们进一步研究了这些分别在CYA/OA中高度突变的已鉴定DMG的人类蛋白质相互作用伙伴，发现网络拓扑和功能作用存在显著差异。值得注意的是，CYA恶性肿瘤表现出广泛的拷贝数改变（CNA）和更多的驱动基因融合。特别是，四个CNA差异基因（即ARID1B、MYB、TP53和ESR1）分别在CYA和OA中作为扩增和缺失过度表达。最终，我们展示了CYA和OA中临床可操作遗传事件的全景比较视图，为与年龄相关的个性化治疗提供了线索。
