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结直肠癌临床病理特征性驱动基因的鉴定及基因亚型分类

Identification of clinicopathological-specific driver gene and genetic subtyping of colorectal cancer.

作者信息

Li Jianjiong, Wang Chunnian, Yang Changshun, Bao Hua, Li Ningyou, Huang Xianqiang, Gong Wei, Hong Xinyue, Yin Jiani C, Pang Jiaohui, Gan Meifu, Yuan Danping

机构信息

Department of Colorectal and Anal Surgery, Ningbo No. 2 Hospital, Ningbo, China.

Department of Pathology, Ningbo Diagnostic Pathology Center, Ningbo, China.

出版信息

Cancer Sci. 2025 Apr;116(4):1068-1081. doi: 10.1111/cas.16432. Epub 2025 Jan 11.

DOI:10.1111/cas.16432
PMID:39797621
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11967266/
Abstract

This study analyzed targeted sequencing data from 6530 tissue samples from patients with metastatic Chinese colorectal cancer (CRC) to identify low mutation frequency and subgroup-specific driver genes, using three algorithms for overall CRC as well as across different clinicopathological subgroups. We analyzed 425 cancer-related genes, identifying 101 potential driver genes, including 36 novel to CRC. Notably, some genes demonstrated subgroup specificity; for instance, ERBB4 was found as a male-specific driver gene and mutations of ERBB4 only influenced the prognosis of male patients with CRC. This sex disparity of ERBB4 was validated in an independent large-scale Memorial Sloan Kettering Cancer Center CRC cohort with 2444 samples. Furthermore, using network-based stratification based on protein-protein interaction, we classified the microsatellite stable (MSS) and unstable (MSI) CRCs into six and three major subtypes, respectively, each showing unique phenotypes and prognoses. In MSS CRC, cluster 5 (APCAMER1-KRAS) and cluster 2 (RNF43-BRAF-PIK3CA) were predominant, and cluster 5 showed a superior overall survival compared with cluster 2. This extensive heterogeneity in driver gene mutations underscores the complexity of CRC and suggests significant implications for treatment and prognostic assessments.

摘要

本研究分析了6530例中国转移性结直肠癌（CRC）患者组织样本的靶向测序数据，采用三种算法对总体CRC以及不同临床病理亚组进行分析，以确定低突变频率和亚组特异性驱动基因。我们分析了425个癌症相关基因，鉴定出101个潜在驱动基因，其中36个是CRC中的新基因。值得注意的是，一些基因表现出亚组特异性；例如，ERBB4被发现是男性特异性驱动基因，ERBB4突变仅影响男性CRC患者的预后。这种ERBB4的性别差异在一个拥有2444个样本的独立大规模纪念斯隆凯特琳癌症中心CRC队列中得到了验证。此外，利用基于蛋白质-蛋白质相互作用的网络分层方法，我们将微卫星稳定（MSS）和不稳定（MSI）CRC分别分为六个和三个主要亚型，每个亚型都表现出独特的表型和预后。在MSS CRC中，第5组（APCAMER1-KRAS）和第2组（RNF43-BRAF-PIK3CA）占主导地位，第5组的总生存期优于第2组。驱动基因突变的这种广泛异质性突出了CRC的复杂性，并提示对治疗和预后评估具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cbd7/11967266/f0b7930ceff6/CAS-116-1068-g001.jpg
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本文引用的文献

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The genomic landscape of 2,023 colorectal cancers.2023 例结直肠癌的基因组图谱。
Nature. 2024 Sep;633(8028):127-136. doi: 10.1038/s41586-024-07747-9. Epub 2024 Aug 7.
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Monitoring tumour resistance to the BRAF inhibitor combination regimen in colorectal cancer patients via circulating tumour DNA.通过循环肿瘤 DNA 监测结直肠癌患者对 BRAF 抑制剂联合方案的肿瘤耐药性。
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RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF metastatic colorectal cancer.
RNF43 突变可预测 BRAF 转移性结直肠癌对 BRAF/EGFR 联合靶向治疗的反应。
Nat Med. 2022 Oct;28(10):2162-2170. doi: 10.1038/s41591-022-01976-z. Epub 2022 Sep 12.
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Comprehensive profiling of 1015 patients' exomes reveals genomic-clinical associations in colorectal cancer.对 1015 名患者外显子组的综合分析揭示了结直肠癌的基因组-临床关联。
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Increasing Incidence of Early-Onset Colorectal Cancer.早发性结直肠癌发病率上升。
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The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection.早发性结直肠癌的上升趋势：流行病学、临床特征、生物学、危险因素、预防及早期检测的综合综述
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