INTRODUCTION Molecular characterization studies revealed recurrent KEAP1/NFE2L2 alterations in non-small cell lung cancer (NSCLC). These genes encode two interacting proteins (stress response pathway, SRP) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations impact on clinical outcomes is unclear. METHODS We performed amplicon-based next-generation sequencing to characterize the SRP in metastatic NSCLC patients (IRE cohort, N=88) treated with first-line chemotherapy. Mutations in the DNA damage response (TP53, ATM and ATR) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of pATR and pATM. Two independent cohorts (MSKCC and TCGA) containing data from ∼1,400 advanced LAC were used to assess the reproducibility of the results. RESULTS In the IRE cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival (PFS) and overall survival (OS) then their wild-type counterparts (log-rank p=0.006 and p=0.018, respectively). This association was driven by LAC where KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of pATR and pATM, in association with a pattern of mutual exclusivity with TP53 alterations. The relationship between KEAP1/NFE2L2 mutations and shorter survival was validated in the MSKCC cohort (N=1,256, log-rank p<0.001) and in the TCGA cohort (N=162, log-rank p=0.039). CONCLUSIONS These findings suggest that mutant SRP represents a negative prognostic/predictive factor in metastatic LAC, and that KEAP1/NFE2L2 mutations may define a molecular subtype of chemo-resistant and rapidly progressing LAC.

中文翻译：

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KEAP1-NFE2L2 通路中的突变定义了快速进展的肺腺癌的分子亚群

引言 分子特征研究揭示了非小细胞肺癌 (NSCLC) 中反复发生的 KEAP1/NFE2L2 改变。这些基因编码两种相互作用的蛋白质（应激反应途径，SRP），介导对氧化应激和异生物质的细胞保护反应。然而，KEAP1/NFE2L2 突变是否影响临床结果尚不清楚。方法我们进行了基于扩增子的下一代测序，以表征接受一线化疗的转移性 NSCLC 患者（IRE 队列，N=88）的 SRP。同时分析了 DNA 损伤反应（TP53、ATM 和 ATR）中的突变。在肺腺癌 (LAC) 中，我们还确定了 pATR 和 pATM 的表达。两个独立的队列（MSKCC 和 TCGA）包含来自约 1,400 名晚期 LAC 的数据，用于评估结果的可重复性。结果 在 IRE 队列中，肿瘤携带 KEAP1/NFE2L2 通路突变的患者的无进展生存期 (PFS) 和总生存期 (OS) 明显低于野生型患者（对数秩 p=0.006 和 p=0.018 ， 分别）。这种关联是由 LAC 驱动的，其中 KEAP1/NFE2L2 突变在快速进展者中过多，并且与疾病进展和死亡风险增加有关。携带 KEAP1/NFE2L2 突变的 LAC 的特征是 pATR 和 pATM 的表达升高，这与 TP53 改变的互斥模式相关。KEAP1/NFE2L2 突变与较短生存期之间的关系在 MSKCC 队列（N=1,256，log-rank p<0.001）和 TCGA 队列（N=162，log-rank p=0.039）中得到验证。