Chen Qingjian, Xu Yu-Hong, Kang Shiyang, Lin WuHao, Luo Linna, Yang Luping, Zhang Qi-Hua, Yang Pan, Huang Jia-Qian, Zhang Xiaoni, Zhang Jing, Zhao Qi, Xu Rui-Hua, Luo Hui-Yan
Department of Medical Oncology Sun Yat Sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat-sen University Guangzhou Guangdong China.
Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer Chinese Academy of Medical Sciences Guangzhou Guangdong China.
MedComm (2020). 2024 Nov 14;5(12):e70011. doi: 10.1002/mco2.70011. eCollection 2024 Dec.
Colorectal adenomas (CRAs) represent precancerous lesions that precede the development of colorectal cancer (CRC). Regular monitoring of CRAs can hinder the progression into carcinoma. To explore the utility of tissue DNA and circulating cell-free DNA (cfDNA) in early diagnosis of CRC, we retrospectively sequenced paired tissue and plasma samples from 85 patients with conventional CRAs. The genetic alterations identified were compared with those from 78 stage-I CRC patients (CRC-I) in the ChangKang project. Within the CRA cohort, we pinpointed 12 genes, notably , , and , that exhibited significant mutated rates in tissue. Patients harboring and mutations displayed persistent polyps. By comparing with the mutational profiles of metastatic CRC plasma samples, we found that was exclusively mutated in CRAs, while and mutations were detected in both CRA and CRC. The presence of cfDNA mutations in plasma was validated through polymerase chain reaction, enhancing the feasibility of using cfDNA mutations for early CRC screening. Compared with CRC-I, CRAs exhibited a reduced frequency of and somatic mutations and underwent non-neutral evolution more often. We established a random forest model based on 15 characteristic genes to distinguish CRA and CRC, achieving an area under the curve of 0.89. Through this endeavor, we identified two novel genes, and , implicated in CRC carcinogenesis. Overall, our findings reveal convincing biomarkers markers for detecting CRAs with a propensity for CRC development, highlighting the importance of early genetic screening in CRC prevention.
结直肠腺瘤（CRAs）是结直肠癌（CRC）发生前的癌前病变。定期监测CRAs可阻碍其向癌的进展。为了探索组织DNA和循环游离DNA（cfDNA）在CRC早期诊断中的作用，我们回顾性地对85例传统CRAs患者的配对组织和血浆样本进行了测序。将鉴定出的基因改变与长康项目中78例I期CRC患者（CRC-I）的基因改变进行比较。在CRA队列中，我们确定了12个基因，特别是 、 和 ，这些基因在组织中表现出显著的突变率。携带 和 突变的患者出现持续性息肉。通过与转移性CRC血浆样本的突变谱进行比较，我们发现 仅在CRAs中发生突变，而 和 突变在CRA和CRC中均有检测到。通过聚合酶链反应验证了血浆中cfDNA突变的存在，提高了使用cfDNA突变进行CRC早期筛查的可行性。与CRC-I相比，CRAs中 和 体细胞突变的频率降低，且更常经历非中性进化。我们基于15个特征基因建立了一个随机森林模型来区分CRA和CRC，曲线下面积达到0.89。通过这项研究，我们确定了两个与CRC致癌作用相关的新基因 和 。总体而言，我们的研究结果揭示了用于检测有发展为CRC倾向的CRAs的令人信服的生物标志物，强调了早期基因筛查在CRC预防中的重要性。
