Wang Feng, Lin Li, Li Zhongkang, Qin Lei, Zhang Shuai, Hu Xueqing, Zhao Yunbo, Huang Yingying
Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Department of Oncology Center, Peking University International Hospital, Beijing, China.
Front Oncol. 2025 Aug 8;15:1608664. doi: 10.3389/fonc.2025.1608664. eCollection 2025.
Heterogeneity of colorectal cancer (CRC) leads to significant differences in Overall Survival (OS). is a new predictive marker for prognosis and anti-/ combinatory therapies of CRC recently. However, few studies focused on the relationship between and co-mutation characteristics and prognosis. This study aims to explore the different prognostic subtypes of -mutated CRC by analyzing the association of clinicopathological and genomic characteristics with survival outcomes.
The clinical characteristics, mutational characteristics, and survival data of CRC patients were obtained for -mutated analysis from cBioPortal. All mutation data were filtered by the 1021-panel (Geneplus-Beijing, China), and the processed data were used to analyze the predictive value of -mutated to OS and concomitant co-mutations. Cox regression analysis was selected to explore prognostic biomarkers, and finally, and MSI were selected for subgroup analysis. The independent validation cohort comprised 339 cases of stage IV CRC from Beijing Hospital.
11 datasets with 4028 patient data were screened for this study. The most common variant was frameshift, which occurred in codon 659-mutated of exon 9, including p.G659Vfs41 (N=116) and p.G659Sfs87 (N=2). codon 659-mutated occurred frequently in right-sided CRC (59.32%, N=70, P<0.0001), and rarely in the left-sided (11.02%, N=13). The incidence of TMB-H in the codon 659-mutated group was 93.22% (110/118), and MSI-H was 78.81% (93/118). Univariate Cox analysis and multivariate Cox analysis showed that MSI-H was the most significantly different biomarker for better prognosis (P=0.004, HR=3, CI 1.4-6.4), and Class 1 V600E was the most different biomarker for worse prognosis (P<0.001, HR=0.3, CI 0.21-0.42). codon 659-mutated with non-class 1 -mutated or MSI-H suggests a better prognosis in CRC. We found that G1 ( codon 659-mutated, non-class 1 -mutated, and MSl-H) had a better PFS and OS. The mutation difference analysis showed that the core genes related to the cancer signaling pathway (PI3K-Akt signaling pathway, MicroRNAs pathway, DNA damage repair, and tumor suppressor genes) were highly frequent in G1. The analysis comparing the core gene mutation difference between -mutated and wild-type in the validation cohort yielded consistent conclusions.
In CRC, we found that the G1 cohort had the best prognosis, and patients with Non-codon 659-mutated, V600E and MSS had the worst prognosis. This may provide clinical value for patients' further accurate prognosis prediction, curative effect prediction, and follow-up management of patients.
结直肠癌（CRC）的异质性导致总生存期（OS）存在显著差异。 是近年来CRC预后及抗/联合治疗的一种新的预测标志物。然而，很少有研究关注 与共突变特征及预后之间的关系。本研究旨在通过分析临床病理和基因组特征与生存结局的关联，探索 -突变型CRC的不同预后亚型。
从cBioPortal获取CRC患者的临床特征、突变特征和生存数据进行 -突变分析。所有突变数据经1021基因panel（中国北京基因加公司）筛选，处理后的数据用于分析 -突变对OS的预测价值及伴随的共突变情况。选择Cox回归分析探索预后生物标志物，最后，选择 和微卫星高度不稳定（MSI）进行亚组分析。独立验证队列包括北京医院的339例IV期CRC病例。
本研究筛选了11个数据集，包含4028例患者数据。最常见的变异是移码突变，发生在外显子9的密码子659突变中，包括 p.G659Vfs41（N = 116）和 p.G659Sfs87（N = 2）。密码子659突变在右侧CRC中频繁发生（59.32%，N = 70，P < 0.0001），而在左侧很少见（11.02%，N = 13）。密码子659突变组中高肿瘤突变负荷（TMB-H）的发生率为93.22%（110/118），MSI-H为78.81%（93/118）。单因素Cox分析和多因素Cox分析表明，MSI-H是预后较好的最显著差异生物标志物（P = 0.004，风险比[HR]=3，置信区间[CI] 1.4 - 6.4），1类 V600E是预后较差的最显著差异生物标志物（P < 0.001，HR = 0.3，CI 0.21 - 0.42）。密码子659突变且非1类 -突变或MSI-H提示CRC预后较好。我们发现G1组（密码子659突变、非1类 -突变和MSI-H）具有更好的无进展生存期（PFS）和OS。突变差异分析表明，与癌症信号通路相关的核心基因（PI3K-Akt信号通路、微小RNA通路、DNA损伤修复和肿瘤抑制基因）在G1组中高频出现。在验证队列中比较 -突变型和野生型之间核心基因突变差异的分析得出了一致的结论。
在CRC中，我们发现G1队列预后最佳，而非密码子659突变、 V600E和微卫星稳定（MSS）的患者预后最差。这可能为患者进一步准确的预后预测、疗效预测及患者的随访管理提供临床价值。
