Colorectal cancer is the second most common malignant tumor worldwide. Analysis of the changes that occur during colorectal cancer progression could provide insights into the molecular mechanisms driving colorectal cancer development and identify improved treatment strategies. In this study, we performed an integrated multiomic analysis of 435 trace tumor samples from 148 patients with colorectal cancer, covering nontumor, intraepithelial neoplasia (IEN), infiltration, and advanced stage colorectal cancer phases. Proteogenomic analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidative phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, which occurred predominantly in the IEN and infiltration phases, respectively, and impacted the cell cycle. Mutations in TP53 were frequent in the advanced stage colorectal cancer phase and associated with the tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of colorectal cancer based on consensus molecular subtype and colorectal cancer intrinsic subtype classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of colorectal cancer based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided colorectal cancer. The AOM/DSS-induced colorectal cancer carcinogenesis mouse model indicated that DDX5 deletion due to chr17q loss promoted colorectal cancer development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of colorectal cancer and identifying the potential therapeutic targets. Significance: Characterization of the proteogenomic landscape of colorectal cancer during progression provides a multiomic map detailing the alterations in each stage of carcinogenesis and suggesting potential diagnostic and therapeutic approaches for patients.

中文翻译：

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全面的蛋白质基因组分析揭示了结直肠癌不同进展阶段的分子特征。


结直肠癌是全球第二常见的恶性肿瘤。对结直肠癌进展过程中发生的变化的分析可以深入了解驱动结直肠癌发展的分子机制并确定改进的治疗策略。在这项研究中，我们对来自 148 名结直肠癌患者的 435 个痕量肿瘤样本进行了综合多组学分析，涵盖非肿瘤、上皮内瘤变 (IEN)、浸润和晚期结直肠癌阶段。蛋白质组学分析表明，KRAS 和 BRAF 突变是相互排斥的，并且 IEN 阶段的氧化磷酸化升高。 Chr17q 丢失和 Chr20q 增加也是相互排斥的，分别主要发生在 IEN 和浸润阶段，并影响细胞周期。 TP53 突变在晚期结直肠癌阶段很常见，并且与肿瘤微环境相关，包括细胞外基质刚性增加和基质浸润。基于共识分子亚型和结直肠癌固有亚型分类的结直肠癌概况分析揭示了每个亚型的进展路径，并表明微卫星不稳定性与特定亚型分类相关。基于位置的结直肠癌分子特征的进一步比较表明，chr10q23.31 的 ANKRD22 扩增增强了右侧结直肠癌的糖酵解。 AOM/DSS 诱导的结直肠癌致癌小鼠模型表明，由于 chr17q 缺失而导致的 DDX5 缺失促进了结直肠癌的发展，这与患者样本的发现一致。 总的来说，这项研究为了解结直肠癌不同阶段的驱动事件和确定潜在的治疗靶点提供了信息资源。意义：结直肠癌进展过程中蛋白质组学景观的表征提供了一个多组学图谱，详细说明了癌发生每个阶段的变化，并为患者提出了潜在的诊断和治疗方法。