具有KRAS突变（KRASmut）的结直肠癌（CRC）通常包括在具有严重代谢失调的共有分子亚型3（CMS3）中。我们探索了KRASmut的转录组影响，关注肿瘤微环境(TME)和代谢失调之外的途径。研究了CRC患者的KRASmut状态，并将总生存期（OS）与野生型KRAS（KRASwt）进行了比较。接下来,我们确定了CMS,并进一步研究了KRASmut的差异表达基因（DEG）和独特的途径。最后,我们使用空间分辨基因表达谱来定义KRASmut在CMS3分类的CRC组织的TME区域中的作用.合并KRASmut的CRC患者主要富集于CMS3。它们在免疫抑制性TME中的免疫基因标记的特异性富集与较差的OS相关。KRASmut激活TGFβ信号与减少的促炎和细胞因子基因特征有关，导致抑制免疫浸润。KRASmutCMS3分类组织的TME区域中的数字空间谱分析表明上调基因，CD40，CTLA4，ARG1，STAT3，IDO，和CD274，这可能是TME免疫抑制的特征。这项研究可能有助于描述KRASmut在免疫抑制性TME中的复杂转录组学特征。结直肠癌患者KRASmut的未来研究和临床试验应考虑这些转录景观。
Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in
consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.
