Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-03-19 DOI:10.1016/j.canlet.2025.217637

Mintao Li , Xuan Gao , Xiangchun Lin , Yan Zhang , Wenying Peng , Tao Sun , Weiyang Shu , Yanyan Shi , Yanfang Guan , Xuefeng Xia , Xin Yi , Yuan Li , Jinzhu Jia

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引用次数: 0

Abstract

Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.

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分析结直肠癌的种系-体细胞突变联系揭示了不同的致瘤模式和一种新的种系突变携带者的预测标记。

在超出临床指南范围的地区进行结直肠癌（CRC）基因检测，揭示了大量可能的致病性种系突变（GMs）。这些通常位于非错配修复（non-mismatch repair, non-MMR）基因中的基因是否以及如何与结直肠癌的肿瘤发生相关，在很大程度上仍未确定。本研究旨在从93种癌症易感基因中鉴定CRC易感基因，并探讨其对CRC体细胞突变特征的潜在影响。我们的第二个目的是研究体细胞ERBB2扩增是否有助于识别GM携带者。本研究共纳入3240名中国结直肠癌患者和10588名对照个体。结直肠癌患者接受配对肿瘤-正常测序与1021个基因面板。进行了病例对照分析，以描述转基因相关的CRC风险。在2405例患者中进行了全面的种系-体关联分析，随后在一个独立的835例患者队列和TCGA CRC队列中验证了主要发现。病例对照结果支持gm在某些同源重组修复（HRR）和DNA损伤检查点因子（CPF）基因（如BRCA1/2、RecQ解旋酶基因、ATM和CHEK2）中的crc易感作用。HRR基因与增加的拷贝数改变负担、更多的TP53克隆突变和更高的携带体细胞ERBB2扩增的可能性相关。据推测，CPF基因与ARID1A和KDM6A体细胞突变在结直肠癌肿瘤发生中具有协同作用。在发病年龄≥55岁、微卫星稳定、无癌症家族史的患者中，ERBB2扩增可显著预测GM携带者。我们的研究结果阐明了不同的种系肿瘤发生模式，而不是由MMR缺陷驱动的。在传统风险特征缺失的情况下，CRC的体细胞ERBB2扩增可作为种系基因检测的指标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.