尽管对CRC异质性的表征得到了改进，临床实践中仍缺乏适当的风险分层工具。该研究旨在阐明与不同转移路线相关的原发肿瘤转录组特征。通过转录组mRNA测序、基因集富集分析(GSEA)和免疫组化对从CRC患者中获取到的仅限于肝脏转移(CRC-Liver)或腹膜转移(CRC-Peritoneum)的原发肿瘤标本进行分析。我们进一步评估了我们的标志在COAD-TCGA独立队列中的临床病理学关联和预后价值。我们发现CRC-Liver组和CRC-Peritoneum组之间一致性分子亚型分布显著不同。基于61个基因的转录组特征能够区分肝脏和腹膜转移路线。GSEA显示CRC-Peritoneum样本中免疫应答和上皮浸润途径的表达较高，而CRC-Liver样本中增殖和代谢途径被激活。我们标志中三个显著差异表达基因(ACE2、CLDN18和DUSP4)在免疫组织化学表达中得到验证，证实了RNA-Seq结果的生物学相关性。COAD-TCGA的体外分析结果显示了CRC-Peritoneum标志与负预后因子以及较差的总体生存和无病生存相关。CRC原发肿瘤向肝脏和腹膜转移表现出明显不同的转录组特征。在临床实践中引入该标志有助于鉴别IV期CRC的新治疗靶点，并为II-III期CRC定义个体化的随访方案。

Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes.Primary tumor specimens obtained from CRC patients with either isolated LM (CRC-Liver) or PM (CRC-Peritoneum) were analyzed by transcriptomic mRNA sequencing, gene set enrichment analyses (GSEA) and immunohistochemistry. We further assessed the clinico-pathological associations and prognostic value of our signature in the COAD-TCGA independent cohort.We identified a significantly different distribution of Consensus Molecular Subtypes between CRC-Liver and CRC-peritoneum groups. A transcriptomic signature based on 61 genes discriminated between liver and peritoneal metastatic routes. GSEA showed a higher expression of immune response and epithelial invasion pathways in CRC-Peritoneum samples and activation of proliferation and metabolic pathways in CRC-Liver samples. The biological relevance of RNA-Seq results was validated by the immunohistochemical expression of three significantly differentially expressed genes (ACE2, CLDN18 and DUSP4) in our signature. In silico analysis of the COAD-TCGA showed that the CRC-Peritoneum signature was associated with negative prognostic factors and poor overall and disease-free survivals.CRC primary tumors spreading to the liver and peritoneum display significantly different transcriptomic profiles. The implementation of this signature in clinical practice could contribute to identify new therapeutic targets for stage IV CRC and to define individualized follow-up programs in stage II-III CRC.