Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer
Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer
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KEAP1/NRF2突变肺癌分子亚型的临床病理学、微环境和遗传决定因素
DOI：
10.1002/ijc.31975
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发表时间：
2019-02-15
影响因子：
6.4
通讯作者：
Fu, Yujie
中科院分区：
文献类型：
--
作者：
Cai, Mei-Chun;Chen, Minjiang;Fu, Yujie
在肺腺癌和鳞状细胞癌中经常检测到体细胞KEAP1-NRF2通路的改变。然而，KEAP1/ nrf2突变型肺癌的生物学特性和分子亚型在很大程度上仍未明确。本研究对携带KEAP1或NFE2L2（编码NRF2）基因突变的原发肿瘤和癌细胞系进行了逐步、综合的分析和实验研究。首先，我们发现KEAP1/ nrf2突变型肺癌具有apobecc介导的突变特征，肿瘤血管生成受损，缺氧应激升高和免疫细胞浸润不足。其次，基于基因表达的亚型分型揭示了KEAP1/ nrf2突变型肺腺癌的三个分子亚群和KEAP1/ nrf2突变型肺鳞状细胞癌的两个分子亚群，每个亚群都具有独特的遗传、分化、免疫学和临床病理特性。第三，单样本预测允许在KEAP1/ nrf2野生型样本中重新鉴定KEAP1/ nrf2活性肿瘤。我们的数据表明，KEAP1/ nrf2突变肺癌是一种微环境独特、生物学异质性和临床被低估的疾病。这些新的病理和分子见解可能会加速开发针对人类恶性肿瘤的有效治疗策略，这些策略以KEAP1-NRF2通路激活为特征。
Somatic KEAP1-NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2-mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2-mutant lung cancer presented APOBEC-mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune-cell infiltrates. Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single-sample prediction allowed for de novo identification of KEAP1/NRF2-active tumors within KEAP1/NRF2-wild-type samples. Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1-NRF2 pathway activation.