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全基因组规模的 CRISPR-Cas9 敲除筛选确定了结直肠癌优化风险分层的适应性评分。

Genome wide-scale CRISPR-Cas9 knockout screens identify a fitness score for optimized risk stratification in colorectal cancer.

机构信息

Department of Hematology and Medical Oncology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Department of coloproctology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

出版信息

J Transl Med. 2024 Jun 10;22(1):554. doi: 10.1186/s12967-024-05323-3.

DOI:10.1186/s12967-024-05323-3
PMID:38858785
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11163718/
Abstract

BACKGROUND: The molecular complexity of colorectal cancer poses a significant challenge to the clinical implementation of accurate risk stratification. There is still an urgent need to find better biomarkers to enhance established risk stratification and guide risk-adapted treatment decisions. METHODS: we systematically analyzed cancer dependencies of 17 colorectal cancer cells and 513 other cancer cells based on genome-scale CRISPR-Cas9 knockout screens to identify colorectal cancer-specific fitness genes. A regression model was built using colorectal cancer-specific fitness genes, which was validated in other three independent cohorts. 30 published gene expression signatures were also retrieved. FINDINGS: We defined a total of 1828 genes that were colorectal cancer-specific fitness genes and identified a 22 colorectal cancer-specific fitness gene (CFG22) score. A high CFG22 score represented unfavorable recurrence and mortality rates, which was validated in three independent cohorts. Combined with age, and TNM stage, the CFG22 model can provide guidance for the prognosis of colorectal cancer patients. Analysis of genomic abnormalities and infiltrating immune cells in the CFG22 risk stratification revealed molecular pathological difference between the subgroups. Besides, drug analysis found that CFG22 high patients were more sensitive to clofibrate. INTERPRETATION: The CFG22 model provided a powerful auxiliary prediction tool for identifying colorectal cancer patients with high recurrence risk and poor prognosis, optimizing precise treatment and improving clinical efficacy.

摘要

背景：结直肠癌的分子复杂性对准确的风险分层的临床实施构成了重大挑战。仍然迫切需要寻找更好的生物标志物，以增强现有的风险分层并指导风险适应的治疗决策。

方法：我们系统地分析了 17 种结直肠癌细胞和 513 种其他癌细胞的癌症依赖性，基于全基因组 CRISPR-Cas9 敲除筛选来鉴定结直肠癌特异性适应性基因。使用结直肠癌特异性适应性基因构建回归模型，并在另外三个独立队列中进行验证。还检索了 30 个已发表的基因表达谱。

结果：我们总共定义了 1828 个结直肠癌特异性适应性基因，并确定了一个 22 个结直肠癌特异性适应性基因（CFG22）评分。高 CFG22 评分代表不利的复发和死亡率，在三个独立队列中得到了验证。与年龄和 TNM 分期相结合，CFG22 模型可为结直肠癌患者的预后提供指导。在 CFG22 风险分层的基因组异常和浸润免疫细胞分析中，揭示了亚组之间的分子病理差异。此外，药物分析发现 CFG22 高患者对氯贝特更敏感。

解释：CFG22 模型为识别高复发风险和预后不良的结直肠癌患者提供了强大的辅助预测工具，可优化精确治疗并提高临床疗效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/ddfd48990e46/12967_2024_5323_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/b6289b6ec1ef/12967_2024_5323_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/6ca4df6411bf/12967_2024_5323_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/207dcc878d83/12967_2024_5323_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/a4b777c7db12/12967_2024_5323_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/cfc138944e3e/12967_2024_5323_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/8507d96ead05/12967_2024_5323_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/ddfd48990e46/12967_2024_5323_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/b6289b6ec1ef/12967_2024_5323_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/6ca4df6411bf/12967_2024_5323_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/207dcc878d83/12967_2024_5323_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/a4b777c7db12/12967_2024_5323_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/cfc138944e3e/12967_2024_5323_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/8507d96ead05/12967_2024_5323_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b762/11163718/ddfd48990e46/12967_2024_5323_Fig7_HTML.jpg

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Genome wide-scale CRISPR-Cas9 knockout screens identify a fitness score for optimized risk stratification in colorectal cancer.

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引用本文的文献

[1]
DiCE: differential centrality-ensemble analysis based on gene expression profiles and protein-protein interaction network.

Nucleic Acids Res. 2025-7-8

[2]
Elucidation of novel diagnostic biomarkers and therapeutic targets in colorectal carcinoma: an integrative approach leveraging multi-omics, computational biology, and single-cell sequencing technologies.

Mamm Genome. 2025-6-25

[3]
Identification and characterization of survival-dependent genes in esophageal cancer via the DepMap database: unraveling their association with immune infiltration.

Discov Oncol. 2025-6-22

[4]
Checkpoint kinase 1 as a promising target in colorectal cancer management.

World J Clin Oncol. 2025-4-24

[5]
RPRD1B's direct interaction with phosphorylated RNA polymerase II regulates polyadenylation of cell cycle genes and drives cancer progression.

RSC Chem Biol. 2025-1-22

本文引用的文献

[1]
Frequent loss of expression in colorectal cancer results in selective dependency.

iScience. 2024-3-29

[2]
Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer.

Cancer Gene Ther. 2024-7

[3]
Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer.

Medicina (Kaunas). 2024-2-26

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The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays.

NPJ Breast Cancer. 2024-3-4

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Molecular pathological classification of colorectal cancer-an update.

Virchows Arch. 2024-2

[6]
Novel molecular classification and prognosis of papillary renal cell carcinoma based on a large-scale CRISPR-Cas9 screening and machine learning.

Heliyon. 2023-12-3

[7]
A novel pipeline for prioritizing cancer type-specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas.

Mol Oncol. 2024-2

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CRISPR/Cas9 system: recent applications in immuno-oncology and cancer immunotherapy.

Exp Hematol Oncol. 2023-11-14

[9]
Large-Scale Databases and Portals on Cancer Genome to Analyze Chaperone Genes Correlated to Patient Prognosis.

Methods Mol Biol. 2023

[10]
Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial.

JAMA Oncol. 2023-9-1

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