Pan-Cancer Analysis of Copy Number Changes in Programmed Death-Ligand 1 (PD-L1, CD274) - Associations with Gene Expression, Mutational Load, and Survival
Pan-Cancer Analysis of Copy Number Changes in Programmed Death-Ligand 1 (PD-L1, CD274) - Associations with Gene Expression, Mutational Load, and Survival
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DOI：
10.1002/gcc.22365
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发表时间：
2016-08-01
影响因子：
3.7
通讯作者：
Stenzinger, Albrecht
中科院分区：
文献类型：
--
作者：
Budczies, Jan;Bockmayr, Michael;Stenzinger, Albrecht
PD-L1（CD 274）- PD-1轴的抑制已经成为一种强大的癌症治疗方法，可以防止肿瘤细胞逃避免疫系统。虽然PD-L1的免疫组织化学检测被引入作为具有可变功效的预测生物标志物，但对影响PD-L1的拷贝数改变（CNA）及其与表达水平，突变负荷和生存的相关性知之甚少。为了获得深入了解，我们使用癌症基因组图谱（TCGA）数据集全面分析了PD-L1 CNA的22种主要癌症类型。我们观察到PD-L1 CNA的多样性，其影响了焦点区域，染色体9 p或整个染色体9。PD-L1缺失比增加更常见（31% vs. 12%），其中缺失在黑色素瘤和非小细胞肺癌中最常见。拷贝数增加最常发生在卵巢癌、头颈癌、膀胱癌、宫颈癌和宫颈内膜癌、肉瘤和结肠直肠癌中。基因结构的精细作图揭示了癌症中特定的重复扩增和缺失的核心区域，具有推定的生物学和临床后果。在许多癌症类型中，PD-L1 CNA与PD-L1 mRNA表达变化显著相关，与非扩增病例相比，PD-L1获得的肿瘤具有显著更高的突变负荷（中位数：78个非同义突变vs. 40个，P = 7.1e-69）。此外，我们观察到，一般而言，PD-L1扩增和缺失均与预后不良相关。总之，PD-L1 CNA，特别是PD-L1拷贝数增加，代表了许多癌症中常见的遗传改变，其影响PD-L1表达水平，与较高的突变负荷相关，并且可用作免疫治疗方案的预测生物标志物。(C)2016 Wiley Periodicals，Inc.
Inhibition of the PD-L1 (CD274) - PD-1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD-L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD-L1 and their associations with expression levels, mutational load, and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD-L1 CNAs. We observed a diverse landscape of PD-L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD-L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non-small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine-mapping of the genetic architecture revealed specific recurrently amplified and deleted core regions across cancers with putative biological and clinical consequences. PD-L1 CNAs correlated significantly with PD-L1 mRNA expression changes in many cancer types, and tumors with PD-L1 gains harbored significantly higher mutational load compared to non-amplified cases (median: 78 non-synonymous mutations vs. 40, P = 7.1e-69). Moreover, we observed that, in general, both PD-L1 amplifications and deletions were associated with dismal prognosis. In conclusion, PD-L1 CNAs, in particular PD-L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD-L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens. (C) 2016 Wiley Periodicals, Inc.