Department of Colorectal Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.
Genet Res (Camb). 2022 Jul 30;2022:1831211. doi: 10.1155/2022/1831211. eCollection 2022.
Colorectal cancer (CRC) is the most prevalent type of malignant tumor of the gastrointestinal tract. In the current study, we characterized the landscape of genomic alterations in CRC patients. Based on the results of whole-exome sequencing (WES), we identified 31 significantly mutated genes. Among them, several genes including TP53, KRAS, APC, PI3KCA, and BRAF were reported as significantly mutated genes in previous studies. In the current study, the most frequently mutated gene was TP53, which encodes tumor suppressor p53, affecting approximately 60% of CRC patients. In addition, we performed the expression profiles of significantly mutated genes between the normal group and tumor groups and identified 20 differentially expressed genes (DEGs); among them, CSMD3, DCHS2, LRP2, RYR2, and ZFHX4 were significantly negatively correlated with PFS. Moreover, consensus clustering analysis for CRC based on the expression of significantly somatic mutated genes was performed. In total, three subtypes of CRC were identified in CRC, including cluster1 ( = 453), cluster2 ( = 158), and cluster 3 ( = 9), based on expression level of significantly somatic mutated genes. Clinicopathological features analysis showed subtype C1 had the longest progression-free survival (PFS) with median time of 8.2 years, while subtypes C2 and C3 had 4.1 and 2.7 years of PFS, respectively. Moreover, we found three subtypes related to tumor infiltration depth, lymph node metastasis, and distant metastasis. Immune infiltration analysis showed the tumor infiltration levels of B cell native, T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell resting, macrophage M0, macrophage M2, myeloid dendritic cell activated, mast cell activated, and mast cell resting significantly changed among the three groups, demonstrating the three subgroups classified by 22 somatically significantly mutated genes had a high capacity to differentiate patients with different immune statuses, which is helpful for the prediction of immunotherapy response of CRC patients. Our findings could provide novel potential predictive indicators for CRC prognosis and therapy targets for CRC immunotherapy.
结直肠癌（CRC）是最常见的胃肠道恶性肿瘤类型。在本研究中，我们对 CRC 患者的基因组改变进行了特征描述。基于全外显子组测序（WES）的结果，我们鉴定出 31 个显著突变基因。其中，TP53、KRAS、APC、PI3KCA 和 BRAF 等几个基因在以前的研究中被报道为显著突变基因。在本研究中，最常突变的基因是 TP53，它编码肿瘤抑制因子 p53，影响约 60%的 CRC 患者。此外，我们对正常组和肿瘤组之间的显著突变基因表达谱进行了分析，鉴定出 20 个差异表达基因（DEGs）；其中，CSMD3、DCHS2、LRP2、RYR2 和 ZFHX4 与 PFS 呈显著负相关。此外，还基于显著体细胞突变基因的表达对 CRC 进行了共识聚类分析。基于显著体细胞突变基因的表达，总共在 CRC 中鉴定出 3 种亚型，包括 cluster1（ = 453）、cluster2（ = 158）和 cluster 3（ = 9）。临床病理特征分析表明，C1 亚型具有最长的无进展生存期（PFS），中位时间为 8.2 年，而 C2 和 C3 亚型的 PFS 分别为 4.1 和 2.7 年。此外，我们还发现了与肿瘤浸润深度、淋巴结转移和远处转移相关的三种亚型。免疫浸润分析表明，在三组中，B 细胞天然、T 细胞 CD8+、T 细胞 CD4+记忆激活、T 细胞γδ、NK 细胞静止、巨噬细胞 M0、巨噬细胞 M2、髓样树突状细胞激活、肥大细胞激活和肥大细胞静止的肿瘤浸润水平显著改变，这表明通过 22 个体细胞显著突变基因分类的三个亚组具有区分不同免疫状态患者的高能力，这有助于预测 CRC 患者的免疫治疗反应。我们的研究结果可为 CRC 预后提供新的潜在预测指标，并为 CRC 免疫治疗提供新的潜在治疗靶点。
