Distinct Molecular Landscape of Epstein-Barr Virus Associated Pulmonary Lymphoepithelioma-Like Carcinoma Revealed by Genomic Sequencing
Distinct Molecular Landscape of Epstein-Barr Virus Associated Pulmonary Lymphoepithelioma-Like Carcinoma Revealed by Genomic Sequencing
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DOI：
10.3390/cancers12082065
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发表时间：
2020-08-01
期刊：
影响因子：
5.2
通讯作者：
To, Ka-Fai
中科院分区：
文献类型：
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作者：
Chau, Shuk-Ling;Tong, Joanna Hung-Man;To, Ka-Fai
肺淋巴上皮瘤样癌（LELC）是一种非小细胞肺癌（NSCLC）亚型，其特征是明显的淋巴细胞浸润并与eb病毒（EBV）有关。这种疾病的分子基础尚不清楚。我们试图通过多种方法研究分子景观，包括全基因组测序，基于捕获的靶向测序，荧光原位杂交和免疫组织化学。在基因组测序之前，通过仔细的显微解剖分离了57个ebv阳性肺上皮细胞的肿瘤细胞。综合分析显示，tp53突变率低（11%），RTK/RAS/RAF（11%）和PI3K/AKT/mTOR通路中已知驱动因素发生率低（7%），但NF-kappa B通路中多个负调节因子的功能丧失突变丰富。程序性细胞死亡配体-1 （PD-L1）高水平表达，在>= 50%和>= 1%肿瘤比例评分时，分别有47%和79%的病例显示PD-L1免疫反应阳性。具有可操作成纤维细胞生长因子受体3 （FGFR3）畸变（4%）和错配修复缺陷（4%）的患者亚群可能符合精准医疗的条件。肺部LELC表现出独特的基因组图谱，不同于主要的非小细胞肺癌亚型，但与ebv相关的鼻咽癌相似。我们的工作有助于了解肺部LELC的分子基础，以探索潜在的治疗选择。
Pulmonary lymphoepithelioma-like carcinoma (LELC) is a subtype of non-small cell lung cancer (NSCLC) characterized by marked lymphocytic infiltration and association with Epstein-Barr virus (EBV). The molecular basis underlying the disease remains unclear. We sought to study the molecular landscape by multiple approaches including whole genomic sequencing, capture-based targeted sequencing, fluorescent in situ hybridization and immunohistochemistry. Tumor cells from 57 EBV-positive pulmonary LELCs were isolated by careful microdissection prior to genomic sequencing. Integrated analysis revealed a distinct genomic landscape of lowTP53mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-kappa B pathway. High level programmed cell death ligand-1 (PD-L1) expression was shown with 47% and 79% of the cases showing positive PD-L1 immunoreactivity at >= 50% and >= 1% tumor proportion score, respectively. Subsets of the patients with actionable fibroblast growth factor receptor 3 (FGFR3)aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine. Pulmonary LELC showed a distinct genomic landscape, different from major NSCLC subtypes but resembled that of EBV-associated nasopharyngeal carcinoma. Our work facilitated the understanding of molecular basis underlying pulmonary LELC to explore potential therapeutic options.