Background: KRAS mutations are detected in ~40% of colorectal cancer (CRC), yet their prognostic value is heterogeneous across specific substitutions; the impact of uncommon variants, particularly in non-metastatic disease, remains uncertain. Methods: We evaluated the prognostic role of the relatively infrequent KRAS G12A substitution in two independent retrospective cohorts of stage II–III CRC treated with surgical resection without neoadjuvant therapy: an institutional series (FMU; n = 299) and a public dataset (AC-ICAM; n = 178). Tumors were genotyped for KRAS (and BRAF in AC-ICAM), and relapse-free survival (RFS) and overall survival (OS) were investigated. Results: KRAS G12A comprised 3.0% (FMU) and 3.4% (AC-ICAM). Across genotypes, G12A showed the highest univariable hazards compared to wild-type (WT) references for both RFS and OS in each cohort. Notably, RFS events among G12A clustered within 12 months of surgery. In multivariable Cox models, G12A remained independently associated with worse RFS and OS in each cohort, whereas non-G12A KRAS mutations did not differ significantly from the WT references. Conclusions: Across two cohorts, KRAS G12A identified a small but clinically meaningful high-risk subset of stage II–III CRC characterized by early recurrence and inferior survival. Recognition of this variant may inform postoperative risk stratification in the adjuvant setting.
背景：约40%的结直肠癌（CRC）可检测到KRAS突变，但其预后价值在不同特定氨基酸置换中存在异质性；罕见变异（尤其在非转移性疾病中）的影响仍不明确。方法：我们在两个独立的II–III期结直肠癌回顾性队列（均接受手术切除且未行新辅助治疗）中评估相对少见的KRAS G12A置换的预后作用：机构队列（FMU；n=299）和公共数据集（AC-ICAM；n=178）。对肿瘤组织进行KRAS（AC-ICAM队列另含BRAF）基因分型，并分析无复发生存期（RFS）与总生存期（OS）。结果：KRAS G12A突变在FMU和AC-ICAM队列中分别占3.0%和3.4%。在所有基因型中，与野生型（WT）参照组相比，G12A在两个队列的RFS和OS单变量分析中均显示最高风险比。值得注意的是，G12A组患者的RFS事件集中发生于术后12个月内。在多变量Cox模型中，G12A在两个队列中均保持与较差RFS和OS的独立相关性，而非G12A的KRAS突变与野生型参照组无显著差异。结论：在两个独立队列中，KRAS G12A突变界定出一个占比虽小但具有临床意义的高风险II–III期结直肠癌亚群，其特征表现为早期复发和生存期缩短。识别该变异可为辅助治疗背景下的术后风险分层提供参考。
KRAS G12A Identifies a High-Risk Subset in Resected Stage II–III Colorectal Cancer
肿瘤(癌症)患者之家