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JAK2/PD-L1/PD-L2(9p24.1)扩增在伴肉瘤样分化的肾细胞癌中的作用:对临床管理的影响。

JAK2/PD-L1/PD-L2 (9p24.1) amplifications in renal cell carcinomas with sarcomatoid transformation: implications for clinical management.

机构信息

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

出版信息

Mod Pathol. 2019 Sep;32(9):1344-1358. doi: 10.1038/s41379-019-0269-x. Epub 2019 Apr 17.

Abstract

Amplifications of JAK2, PD-L1, and PD-L2 at 9p24.1 lead to constitutive expression of PD-L1. This, coupled with JAK2-activation dependent upregulation of PD-L1 and adaptive/induced expression leads to higher tumor PD-L1 expression and immune evasion. Renal tumors were therefore evaluated for 9p24.1 amplifications. A combination of next generation sequencing-based copy number analysis, fluorescence in situ hybridization for JAK2/INSL6 and PD-L1/PD-L2 and immunohistochemistry for phospho-STAT3 (downstream target of JAK2), PD-L1, PD-L2, and PD-1 was performed. In this study we interrogated a "Discovery" cohort of 593 renal tumors, a "Validation" cohort of 398 high-grade renal tumors, The Cancer Genome Atlas (879 cases) and other public datasets (846 cases). 9p24.1 amplifications were significantly enriched in renal tumors with sarcomatoid transformation (5.95%, 15/252) when compared to all histologic subtypes in the combined "Discovery", "Validation" and public datasets (16/2636, 0.6%, p < 0.00001). Specifically, 9p24.1 amplifications amongst sarcomatoid tumors in public datasets, the "Discovery" and "Validation" cohorts were 7.7% (6/92), 15.1% (5/33), and 3.1% (4/127), respectively. Herein, we describe 13 cases and amplification status for these was characterized using next generation sequencing (n = 9) and/or fluorescence in situ hybridization (n = 10). Correlation with PD-L1 immunohistochemistry (n = 10) revealed constitutive expression (mean H-score: 222/300, n = 10). Analysis of outcomes based on PD-L1 expression in tumor cells performed on 282 cases ("Validation" cohort) did not reveal a significant prognostic effect and was likely reflective of advanced disease. A high incidence of constitutive PD-L1 expression in tumor cells in the "Validation" cohort (H-Score ≥250/300) was noted amongst 83 rhabdoid (6%) and 127 sarcomatoid renal tumors (7.1%). This suggests additional mechanisms of constitutive expression other than amplification events. Importantly, two patients with 9p24.1-amplified sarcomatoid renal tumors showed significant response to immunotherapy. In summary, a subset of renal tumors with sarcomatoid transformation exhibits constitutive PD-L1 overexpression and these patients should be evaluated for enhanced response to immunotherapy.

摘要

9p24.1 处 JAK2、PD-L1 和 PD-L2 的扩增导致 PD-L1 的组成性表达。这与 JAK2 激活依赖性 PD-L1 的上调以及适应性/诱导性表达相结合,导致肿瘤 PD-L1 表达和免疫逃逸更高。因此,对肾肿瘤进行了 9p24.1 扩增评估。进行了下一代测序的基于拷贝数分析、JAK2/INSL6 和 PD-L1/PD-L2 的荧光原位杂交以及磷酸化 STAT3(JAK2 的下游靶标)、PD-L1、PD-L2 和 PD-1 的免疫组化的组合。在这项研究中,我们研究了一个“发现”队列中的 593 例肾肿瘤、一个“验证”队列中的 398 例高级别肾肿瘤、癌症基因组图谱(879 例)和其他公共数据集(846 例)。与联合“发现”、“验证”和公共数据集的所有组织学亚型相比,具有肉瘤样转化的肾肿瘤中 9p24.1 扩增明显丰富(5.95%,15/252)(p<0.00001)。具体而言,在公共数据集、“发现”和“验证”队列中,肉瘤样肿瘤中的 9p24.1 扩增分别为 7.7%(6/92)、15.1%(5/33)和 3.1%(4/127)。在此,我们描述了 13 例病例,并使用下一代测序(n=9)和/或荧光原位杂交(n=10)对这些病例的扩增状态进行了表征。与肿瘤细胞中 PD-L1 免疫组化的相关性(n=10)显示出组成性表达(平均 H 评分:222/300,n=10)。对 282 例病例(“验证”队列)进行的基于肿瘤细胞中 PD-L1 表达的生存分析没有显示出显著的预后效果,这可能反映了晚期疾病。在“验证”队列中,在肿瘤细胞中观察到 PD-L1 的高发生率(H 评分≥250/300)(83 例横纹肌样(6%)和 127 例肉瘤样肾肿瘤(7.1%)。这表明除了扩增事件之外,还有其他导致组成性表达的机制。重要的是,两名 9p24.1 扩增的肉瘤样肾肿瘤患者对免疫治疗有明显反应。总之,具有肉瘤样转化的肾肿瘤亚群表现出组成性 PD-L1 过表达,这些患者应评估对免疫治疗的增强反应。

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