泛omics 揭示了患者个体性是结直肠癌进展的主要驱动因素。

Panomics reveals patient individuality as the major driver of colorectal cancer progression.

机构信息

Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.

Medical Systems Biology Group, Lübeck Institute Für Experimental Dermatology, University of Lübeck, Campus Lübeck, 23538, Lübeck, Germany.

出版信息

J Transl Med. 2023 Jan 23;21(1):41. doi: 10.1186/s12967-022-03855-0.

DOI:10.1186/s12967-022-03855-0

PMID:36691026

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9869555/

Abstract

BACKGROUND

Colorectal cancer (CRC) is one of the most prevalent cancers, with over one million new cases per year. Overall, prognosis of CRC largely depends on the disease stage and metastatic status. As precision oncology for patients with CRC continues to improve, this study aimed to integrate genomic, transcriptomic, and proteomic analyses to identify significant differences in expression during CRC progression using a unique set of paired patient samples while considering tumour heterogeneity.

METHODS

We analysed fresh-frozen tissue samples prepared under strict cryogenic conditions of matched healthy colon mucosa, colorectal carcinoma, and liver metastasis from the same patients. Somatic mutations of known cancer-related genes were analysed using Illumina's TruSeq Amplicon Cancer Panel; the transcriptome was assessed comprehensively using Clariom D microarrays. The global proteome was evaluated by liquid chromatography-coupled mass spectrometry (LC‒MS/MS) and validated by two-dimensional difference in-gel electrophoresis. Subsequent unsupervised principal component clustering, statistical comparisons, and gene set enrichment analyses were calculated based on differential expression results.

RESULTS

Although panomics revealed low RNA and protein expression of CA1, CLCA1, MATN2, AHCYL2, and FCGBP in malignant tissues compared to healthy colon mucosa, no differentially expressed RNA or protein targets were detected between tumour and metastatic tissues. Subsequent intra-patient comparisons revealed highly specific expression differences (e.g., SRSF3, OLFM4, and CEACAM5) associated with patient-specific transcriptomes and proteomes.

CONCLUSION

Our research results highlight the importance of inter- and intra-tumour heterogeneity as well as individual, patient-paired evaluations for clinical studies. In addition to changes among groups reflecting CRC progression, we identified significant expression differences between normal colon mucosa, primary tumour, and liver metastasis samples from individuals, which might accelerate implementation of precision oncology in the future.

摘要

背景

结直肠癌（CRC）是最常见的癌症之一，每年新发病例超过 100 万例。总的来说，CRC 的预后在很大程度上取决于疾病的阶段和转移状态。随着 CRC 患者的精准肿瘤学的不断进步，本研究旨在整合基因组、转录组和蛋白质组分析，同时考虑肿瘤异质性，使用独特的配对患者样本识别 CRC 进展过程中表达的显著差异。

方法

我们分析了严格低温条件下制备的新鲜冷冻组织样本，这些样本来自同一患者的匹配健康结肠黏膜、结直肠腺癌和肝转移灶。使用 Illumina 的 TruSeq 扩增癌症面板分析已知癌症相关基因的体细胞突变；使用 Clariom D 微阵列全面评估转录组。通过液相色谱-串联质谱（LC-MS/MS）评估全局蛋白质组，并通过二维差异凝胶电泳进行验证。随后根据差异表达结果计算非监督主成分聚类、统计比较和基因集富集分析。

结果

尽管 panomics 显示与健康结肠黏膜相比，恶性组织中 CA1、CLCA1、MATN2、AHCYL2 和 FCGBP 的 RNA 和蛋白质表达水平较低，但在肿瘤和转移组织之间未检测到差异表达的 RNA 或蛋白质靶标。随后的患者内比较显示出与患者特定转录组和蛋白质组相关的高度特异性表达差异（例如，SRSF3、OLFM4 和 CEACAM5）。