KEAP1/NFE2L2通路特征优于KEAP1/NFE2L2-突变状态，并揭示了非小细胞肺癌中的替代通路激活突变

2023-08-03 09:52

K1N2评分通过检测KEAP1/NFE2L2mut病例并发现替代的基因组激活剂来鉴定KEAP1/NFC2L2激活的NSCLC。它是筛选具有组成型活性KEAP1/NFE2L2通路的患者的潜在手段。

SCI

2 August 2023

KEAP1/NFE2L2 pathway signature outperforms KEAP1/NFE2L2 mutation status and reveals alternative pathway-activating mutations in Non-Small Cell Lung Cancer

(Journal of Thoracic Oncology, IF: 20.4)

C. Arolt, M. Dugan, R. Wild, V. Richartz, B. Holz, A.H. Scheel, J. Bragelmann, S. Wagener-Ryczek, S. Merkelbach-Bruse, J. Wolf, R. Buettner, L. Catanzariti, M. Scheffler, A.M. Hillmer

CORRESPONDENCE TO: ahillmer@uni-koeln.de

Background 背景

Activation of the antioxidant KEAP1/NFE2L2(NRF2)-pathway leads to increased glutamine dependence and an aggressive phenotype in non-small cell lung cancer (NSCLC). Since this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors.

抗氧化剂KEAP1/NFE2L2（NRF2）途径的激活导致非小细胞肺癌（NSCLC）中谷氨酰胺依赖性增加和侵袭性表型。由于该途径已被探索为临床靶点，我们开发了一种用于鉴定KEAP1/NFE2L2活化肿瘤的转录组学标记。

Material and methods 材料和方法

A total of 971 NSCLC were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations. 348 in-house NSCLC were analyzed using a NanoString expression panel for validation.

共使用971个NSCLC患者数据来训练表达特征（K1N2评分）以预测KEAP1/NFE2L2突变。使用NanoString表达面板对348个内部NSCLC进行分析以进行验证。

Results 发现

The 46-gene K1N2-score robustly predicted KEAP1/NFE2L2 mutations in the validation set irrespective of histology and mutation (AUC: 89.5, sensitivity: 90.2%), suggesting that ~90% of KEAP1/NFE2L2-mutations are pathway-activating. The K1N2-score outperformed KEAP1/NFE2L2 mutational status when predicting patient survival (score p=0.047; mutation p=0.215). In K1N2-score-positive, but KEAP1/NFE2L2wt samples, enrichment testing identified SMARCA4/BRG1 and CUL3 mutations as mimics of KEAP1/NFE2L2 mutations.

总计46基因的K1N2评分有力地预测了验证集中的KEAP1/NFE2L2突变，而与组织学和突变无关（AUC:89.5，灵敏度：90.2%），表明约90%的KEAP1/NFE2L2变异是通路激活的。在预测患者存活率时，K1N2评分优于KEAP1/NFE2L2突变状态（评分p=0.047；突变p=0.215）。在K1N2评分为阳性但KEAP1/NFC2L2wt样本中，富集测试确定SMARCA4/BRG1和CUL3突变是KEAP1/NF-2L2突变的模拟物。

Conclusions 结论

The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.

K1N2评分通过检测KEAP1/NFE2L2mut病例并发现替代的基因组激活剂来鉴定KEAP1/NFC2L2激活的NSCLC。它是筛选具有组成型活性KEAP1/NFE2L2通路的患者的潜在手段。