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    转录组测序分析STK11mutTP53wtKRASmut突变型肺癌微环境中免疫浸润及抗氧化通路的特征

    Transcriptomic Profiling Characteristics of Immune Infiltration and Antioxidant Pathway in STK11mutTP53wtKRASmut Lung Cancers

      摘要
    • 摘要:
      目的 KRAS基因突变是非小细胞肺癌（non-small cell lung cancer，NSCLC）的特定分子亚型。目前KRAS G12C抑制剂已获批用于临床，但疗效有限，针对其他KRAS突变亚型的靶向药物正在研发中。为深入解析疾病机制并指导精准治疗，我们分析了KRAS突变型（KRASmut）NSCLC的微环境中免疫浸润及抗氧化通路的特征。
      方法 对KRASmut NSCLC的肿瘤标本进行组织病理学评估后，提取DNA和RNA样本，完成肿瘤523基因全景变异分析和转录组测序分析。
      结果 二代测序（next-generation sequencing，NGS）结果显示，162例KRASmut NSCLC包括68例G12C、33例G12D、32例G12V、9例G12A、6例G13D、6例Q61H/L和8例其他突变亚型。常见的共突变基因包括TP53、LRP1B、STK11（LKB1）、KEAP1、SPTA1、PTPRD、MGA、FAT1和RBM10。TP53是最常见的共突变基因（n=94，58.0%），其次是STK11（n=47，29.0%）和STK11/TP53双重共突变（n=15，9.3%）。根据KRAS、TP53和STK11的共突变模式，样本分为四组：KO（仅KRAS突变，n=36）、KP（TP53mutKRASmut，n=79）、KL（STK11mutTP53wtKRASmut，n=32）和KM（STK11mutTP53mutKRASmut，n=15）。STK11突变的样本STK11表达量低。KL组KEAP1突变显著性富集（P=1.8×10−3）；NRF2调控激活，基因集富集分析（gene set enrichment analysis，GSEA）显示NRF2调控基因显著富集（P=5.6×10−8），AKR1C1/2、GCLC、GPX2、GSTP1、NQO1、PGD、SLC7A11和 PRDX1等NRF2调控相关基因表达水平显著高于其他各组（P<0.05）；CD274（PD-L1）表达水平显著低于其他各组（P=4×10−4），免疫评分偏低，呈现“免疫冷”的特征。
      结论 STK11mutTP53wtKRASmut（KL亚型）肺癌是一种独特的生物学亚型，具有“免疫冷”、NRF2抗氧化通路激活、基因组不稳定等生物学特征，该结果为在临床优化KRAS突变型NSCLC精准诊疗策略提供了科学数据。

       

      Abstract:
      Background KRAS mutations define a molecular subgroup of non-small cell lung cancer (NSCLC). KRAS G12C inhibitors have been approved in clinic, yet with limited efficacy, and inhibitors targeting other KRAS mutation subtypes are under development. Further investigation of cellular and molecular components of KRAS-mutant (KRASmut) NSCLC is warranted to understand the disease mechanisms and guide precise treatment.
      Methods After histopathological evaluation of tumor specimens from KRASmut NSCLC, DNA and RNA were extracted. Comprehensive genomic and transcriptomic profiling of KRASmut NSCLC was performed.
      Results Next-generation sequencing (NGS) results showed that, Among 162 cases of KRASmut NSCLC, subtypes of KRAS mutations included G12C (n=68), G12D (n=33), G12V (n=32), G12A (n=9), G13D (n=6), Q61H/L (n=6) and others (n=8). Frequent co-mutations occurred in TP53, LRP1B, STK11(LKB1), KEAP1, SPTA1, PTPRD, MGA, FAT1, and RBM10. TP53 was the most commonly co-mutated gene (n=94, 58.0%), followed by STK11 (n=47, 29.0%) and dual STK11/TP53 co-mutation (n=15, 9.3%). Based on the co-mutation patterns of KRAS, TP53, and STK11, samples were classified into four groups: KO (KRASmut-only, n=36), KP (TP53mutKRASmut, n=79), KL (STK11mutTP53wtKRASmut, n=32) and KM (STK11mutTP53mutKRASmut, n=15). The expression of STK11 was low in STK11mut samples. In KL group, KEAP1 mutation was significantly enriched (P=1.8×10−3), NRF2 regulation was activated, gene set enrichment analysis (GSEA) enrichment analysis showed that NRF2 regulation genes were significantly enriched (P=5.6×10−8), the expression levels of NRF2 regulation related genes such as AKR1C1/2, GCLC, GPX2, GSTP1, NQO1, PGD, SLC7A11, and PRDX1 were significantly higher than those in other groups (P<0.05), the expression level of CD274 was significantly lower than that of other groups (P=4×10−4), and the immune score was low, showing a cold immune characteristic.
      Conclusions STK11mutTP53wtKRASmut (KL) lung cancer is a unique biological subtype, having biological characteristics of cold immunity, NRF2 anti-oxidation activation and genomic instability. The results provide scientific insight for clinical optimization of precise diagnosis and treatment strategy in KRASmut NSCLC.

       

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