Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Colorectal Institute of Nanjing Medical University, Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine.
Nanjing Geneseeq Technology Inc., School of Public Health, Nanjing Medical University.
Int J Surg. 2024 Aug 1;110(8):4559-4570. doi: 10.1097/JS9.0000000000001584.
Early-onset colorectal cancer (EOCRC) is associated with a poorer prognosis relative to late-onset colorectal cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC.
A total of 11 344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10 766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel).
Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status.
This study revealed a significantly higher MSI-H distribution rate in EOCRC, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.
早发性结直肠癌（EOCRC）的预后相对较差，而迟发性结直肠癌（LOCRC）的预后较好，近年来其发病率逐渐上升。这就需要全面研究其潜在的发病机制，并确定针对 EOCRC 患者的治疗靶点。本研究旨在通过将 EOCRC 与 LOCRC 进行对比，描绘 EOCRC 的独特分子特征。
本研究共纳入了 2003 年至 2022 年间诊断的 11344 例结直肠癌患者，其中包括 578 例 EOCRC 病例和 10766 例 LOCRC 病例。采用下一代测序技术评估这些患者的肿瘤相关突变和肿瘤突变负荷（TMB）。采用免疫组织化学法检测 PD-L1 表达。采用毛细管电泳法（2B3D NCI 试剂盒）检测微卫星不稳定性（MSI）。
与 LOCRC 患者相比，EOCRC 患者的 TNM 分期较晚，肿瘤分化程度较低，组织学类型较差。在 LOCRC 患者中，MSI-H 状态的患者的 TNM 分期早于 MSI-L/MSS 状态的患者。值得注意的是，EOCRC 中 MSI-H 的发生率明显高于 LOCRC（10.2% vs. 2.2%）。7 基因panel（ARID1A、FANCI、CASP8、DGFRA、DPYD、TSHR 和 PRKCI）的突变在 LOCRC 中更为常见。在 EOCRC 队列中，MSI-H 亚型的患者 TNM 分期较早，但组织分化较差，黏液性腺癌的发生率较高。在 EOCRC 患者中，FBXW7、FAT1、ATM、ARID1A 和 KMT2B 突变在 MSI-H 亚组中明显富集。对 MSI-H 患者的比较分析显示，在 EOCRC 组中，FGFBR2、PBRM1、RNF43、LRP1B、FBXW7、ATM 和 ARID1A 的突变频率更高。此外，EOCRC 患者的总体 TMB 较高，特别是在 MSI-H 亚型中。PD-L1 的表达在 EOCRC 中升高，并与 MSI 状态呈正相关。
本研究表明，EOCRC 中 MSI-H 的分布率明显较高，且 EOCRC 具有独特的突变特征，并伴有较高的 PD-L1 表达。这些发现有望为 EOCRC 患者的个体化治疗策略提供指导，改善疾病管理。
