近日，美国威尔康奈尔医学院Rohit Chandwani及其小组揭示人类胰腺癌中特定KRAS突变的不同临床结果与生物特征。这一研究成果于2024年8月29日在线发表在国际学术期刊《癌细胞》上。

研究人员检查了1360名连续接受外科切除的胰腺导管腺癌（PDAC）患者，发现KRAS^G12R突变在早期（I期）疾病中富集，这并不是由于肿瘤体积较小，而是由于较高的淋巴结阴性率。与KRAS^G12D相比，KRAS^G12R肿瘤与较少的远处复发和更高的生存率相关。

为了理解其生物学基础，研究人员对20名患者进行了空间分析，并对100个肿瘤样本进行了RNA测序，结果显示KRAS^G12D肿瘤中增强了致癌信号和上皮-间质转化（EMT），而KRAS^G12R肿瘤中则显示出增加的核因子κB（NF-κB）信号。

对小鼠Kras^G12R PDAC类器官的研究表明，在原位模型中，这些肿瘤的迁移能力降低，生存率提高。因此，PDAC中的KRAS突变与不同的临床表现、临床结果和生物学行为相关，突显了突变分析的预后价值以及详细研究特定突变PDAC生物学的重要性。

研究人员表示，PDAC中的KRAS突变可能在致癌性上存在差异，但对人类患者的具体影响尚未得到深入探讨。

附：英文原文

Title: Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Author: Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Shauna L. Houlihan, Alicia Alonso, Erika Hissong, George M. Church, Christopher E. Mason, Despina Siolas, Faiyaz Notta, Mithat Gonen, Lukas E. Dow, William R. Jarnagin, Rohit Chandwani

Issue&Volume: 2024-08-29

Abstract: 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.

DOI: 10.1016/j.ccell.2024.08.002

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00296-4