Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Yanta West Road 277, Xi'an, 710061, Shaanxi, China.
Eur J Med Res. 2024 Mar 28;29(1):207. doi: 10.1186/s40001-024-01805-8.
Colorectal cancer (CRC) is a complex malignancy characterized by diverse molecular profiles, clinical outcomes, and limited precision in prognostic markers. Addressing these challenges, this study utilized multi-omics data to define consensus molecular subtypes in CRC and elucidate their association with clinical outcomes and underlying biological processes.
Consensus molecular subtypes were obtained by applying ten integrated multi-omics clustering algorithms to analyze TCGA-CRC multi-omics data, including mRNA, lncRNA, miRNA, DNA methylation CpG sites, and somatic mutation data. The association of subtypes with prognoses, enrichment functions, immune status, and genomic alterations were further analyzed. Next, we conducted univariate Cox and Lasso regression analyses to investigate the potential prognostic application of biomarkers associated with multi-omics subtypes derived from weighted gene co-expression network analysis (WGCNA). The function of one of the biomarkers MID2 was validated in CRC cell lines.
Two CRC subtypes linked to distinct clinical outcomes were identified in TCGA-CRC cohort and validated with three external datasets. The CS1 subtype exhibited a poor prognosis and was characterized by higher tumor-related Hallmark pathway activity and lower metabolism pathway activity. In addition, the CS1 was predicted to have less immunotherapy responder and exhibited more genomic alteration compared to CS2. Then a prognostic model comprising five genes was established, with patients in the high-risk group showing substantial concordance with the CS1 subtype, and those in the low-risk group with the CS2 subtype. The gene MID2, included in the prognostic model, was found to be correlated with epithelial-mesenchymal transition (EMT) pathway and distinct DNA methylation patterns. Knockdown of MID2 in CRC cells resulted in reduced colony formation, migration, and invasion capacities.
The integrative multi-omics subtypes proposed potential biomarkers for CRC and provided valuable knowledge for precision oncology.
结直肠癌（CRC）是一种具有复杂分子特征的恶性肿瘤，其临床结局多样，预后标志物的精准度有限。为了应对这些挑战，本研究利用多组学数据定义了结直肠癌的共识分子亚型，并阐明了它们与临床结局和潜在生物学过程的关系。
通过应用十种集成的多组学聚类算法对 TCGA-CRC 多组学数据（包括 mRNA、lncRNA、miRNA、DNA 甲基化 CpG 位点和体细胞突变数据）进行分析，得到共识分子亚型。进一步分析了亚型与预后、富集功能、免疫状态和基因组改变的关联。然后，我们进行了单变量 Cox 和 Lasso 回归分析，以研究与加权基因共表达网络分析（WGCNA）衍生的多组学亚型相关的生物标志物在预后中的潜在应用。在 CRC 细胞系中验证了一个生物标志物 MID2 的功能。
在 TCGA-CRC 队列中确定了两种与不同临床结局相关的 CRC 亚型，并在三个外部数据集进行了验证。CS1 亚型预后不良，其特征是肿瘤相关的标志性途径活性较高，代谢途径活性较低。此外，CS1 预计免疫治疗应答者较少，与 CS2 相比，基因组改变更多。然后建立了一个包含五个基因的预后模型，高风险组的患者与 CS1 亚型高度一致，低风险组的患者与 CS2 亚型一致。包含在预后模型中的基因 MID2 与上皮-间充质转化（EMT）途径和独特的 DNA 甲基化模式相关。CRC 细胞中 MID2 的敲低导致集落形成、迁移和侵袭能力降低。
提出的整合多组学亚型为 CRC 提供了潜在的生物标志物，并为精准肿瘤学提供了有价值的知识。
