Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies.
Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies.
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DOI：
10.1200/po.17.00235
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发表时间：
2018
影响因子：
4.6
通讯作者：
Kurzrock R
中科院分区：
文献类型：
--
作者：
Kato S;Ross JS;Gay L;Dayyani F;Roszik J;Subbiah V;Kurzrock R
MDM2扩增可通过抑制P53直接或间接促进肿瘤的发生。MDM2具有越来越高的临床相关性，因为抑制剂正在临床试验中进行评估，并且MDM2扩增可能是抗PD-1/PD-L1免疫治疗后加速进展的基因组相关性，即所谓的超进展。我们使用下一代测序(NGS)来确定MDM2在大量不同癌症中的扩增状态。我们使用临床级别的NGS(182到465个基因)询问了102,878名不同恶性肿瘤患者的MDM2扩增和共改变基因的分子图谱。3.5%的患者(3,650/102,878)出现MDM2扩增。大多数肿瘤类型都有一小部分MDM2扩增患者。大多数患者(99.0%[3,613/3,650])有伴随MDM2扩增的共改变。涉及多种途径，包括酪氨酸激酶(37.9%[1,385/3650])、PI3K信号转导(25.4%[926/3650])、TP53(24.9%[910/3650])和MAPK信号转导(23.6%[863/3650])。尽管不常见，错配修复基因和PD-L1扩增也是共改变的(2.2%[3,650例中的79例])。大多数患者(97.6%[3,650人中的3,563人])有一个或多个可能与食品和药物管理局批准的或研究用药靶向的联合改变。与MDM2野生型人群相比，MDM2扩增与高肿瘤突变负担相关的频率较低(2.9%vs6.5%；P<；.001)。一个说明性的患者谁持有MDM2扩增和经历了免疫检查点抑制剂的高度进展。在102,878名患者中发现了3.5%的MDM2扩增，其中97.6%的患者存在潜在的靶向基因组共改变。这项研究表明，大多数肿瘤类型中的一小部分存在MDM2扩增和药理上容易处理的共改变。
MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.