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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。

Comprehensive profiling of 1015 patients' exomes reveals genomic-clinical associations in colorectal cancer.

机构信息

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China.

HaploX Biotechnology, Co., Ltd., 8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan District, Shenzhen, Guangdong, 518057, P. R. China.

出版信息

Nat Commun. 2022 Apr 29;13(1):2342. doi: 10.1038/s41467-022-30062-8.

DOI:10.1038/s41467-022-30062-8
PMID:35487942
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9055073/
Abstract

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

摘要

由于目前研究中样本量有限或靶向基因有限，结直肠癌 (CRC) 的遗传基础及其临床相关性仍了解甚少。在这里，我们对 1015 名 CRC 患者进行了超深度全外显子组测序，作为 ChangKang 项目的一部分。我们鉴定了 46 个高置信度的显著突变基因，其中 8 个基因在 14.9%的患者中发生突变：LYST、DAPK1、CR2、KIF16B、NPIPB15、SYTL2、ZNF91 和 KIAA0586。通过无监督聚类算法，我们提出了一种亚分型策略，将 CRC 患者分为具有不同临床特征的四个基因组亚型：高度突变型、染色体不稳定性高风险型、染色体不稳定性低风险型和基因组稳定性型。免疫原性分析揭示了免疫原性降低与基因组亚型和 CRC 预后不良之间的关联。此外，我们发现线粒体 DNA 拷贝数是预测 CRC 生存结果的独立因素。总体而言，我们的研究结果为 CRC 提供了相关的分子特征，为临床实践和转化研究提供了有价值的资源。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3749/9055073/e3168788d5d4/41467_2022_30062_Fig7_HTML.jpg
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Expert opinions on immunotherapy for patients with colorectal cancer.
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