胰腺导管腺癌 (PDAC) 中的 KRAS 突变被认为具有不同的致癌性，但其对人类患者的影响尚未深入探讨。我们检查了 1,360 名连续接受手术切除的 PDAC 患者，发现 KRASG12R 突变在早期（I 期）疾病中丰富，这不是因为肿瘤尺寸较小，而是因为淋巴结阴性增加。与 KRASG12D 相比，KRASG12R 肿瘤与远处复发减少和生存率提高相关。为了了解其生物学基础，我们对 20 名患者进行了空间分析，并对 100 个肿瘤进行了批量 RNA 测序，发现 KRASG12D 中致癌信号传导和上皮间质转化 (EMT) 增强，而 KRASG12R 肿瘤中核因子 κB (NF-κB) 信号传导增强。对小鼠 KrasG12R PDAC 类器官的正交研究表明，原位模型中的迁移减少，存活率提高。因此，PDAC 中的 KRAS 改变与不同的表现、临床结果和生物学行为相关，突出了突变分析的预后价值以及阐明突变特异性 PDAC 生物学的重要性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.Copyright © 2024 Elsevier Inc. All rights reserved.