Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2-mutant lung cancer

作者：Cai Mei Chun; Chen Minjiang; Ma Pengfei; Wu Jie; Lu Haijiao; Zhang Shengzhe; Liu Jin; Zhao Xiaojing; Zhuang Guanglei^*; Yu Zhuang^*; Fu Yujie^*

来源：International Journal of Cancer, 2019, 144(4): 788-801.

DOI：10.1002/ijc.31975

• lung cancer
• KEAP1
• NRF2
• molecular subtypes
• microenvironment

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.

• 单位
  中国医学科学院; 中国医学科学院北京协和医院; 青岛大学; 上海交通大学