Lu Can, Zhang Xiaopeng, Schardey Josefine, Wirth Ulrich, Heinrich Kathrin, Massiminio Luca, Cavestro Giulia Martina, Neumann Jens, Bazhin Alexandr V, Werner Jens, Kühn Florian
Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention (Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
NPJ Precis Oncol. 2023 Jul 1;7(1):63. doi: 10.1038/s41698-023-00414-8.
The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
早发性结直肠癌（EO-CRC，指年龄小于50岁的患者）的发病率在全球范围内呈上升趋势。EO-CRC患者的特定基因特征在很大程度上尚不清楚。由于微卫星不稳定的EO-CRC常与林奇综合征相关，我们旨在全面表征微卫星稳定的EO-CRC（MSS-EO-CRC）的肿瘤微环境（TME）和基因表达谱。在此，我们证明MSS-EO-CRC在肿瘤浸润免疫细胞模式、免疫治疗反应、共识分子亚型和预后方面与微卫星稳定的晚发性结直肠癌（MSS-LO-CRC）相似。133个差异表达基因被确定为MSS-EO-CRC的独特基因特征。此外，我们建立了一个风险评分，其与PD-L1表达呈正相关，并且能够反映肿瘤浸润免疫细胞水平和MSS-EO-CRC患者的预后。将该评分应用于抗PD-L1治疗队列表明，低风险评分组具有显著的治疗优势和临床益处。此外，在MSS-EO-CRC患者的不同发病部位鉴定出了候选驱动基因。总之，MSS-EO-CRC表现出与MSS-LO-CRC不同的独特分子特征，尽管它们具有相似的TME特征和生存模式。我们的风险评分似乎足以预测预后和免疫治疗反应，因此有助于优化MSS-EO-CRC的治疗。
