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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2024-08-29 DOI:10.1016/j.ccell.2024.08.002

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, Rohit Chandwani

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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 KRAS^G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS^G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS^G12D. 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 KRAS^G12D and increased nuclear factor κB (NF-κB) signaling in KRAS^G12R tumors. Orthogonal studies of mouse Kras^G12R 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.

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人类胰腺癌中特定 KRAS 突变体的不同临床结果和生物学特征

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得到深入探讨。我们对接受手术切除的 1,360 例连续的 PDAC 患者进行了研究，发现 KRASG12R 突变富集于早期（I 期）疾病，这并不是因为肿瘤较小，而是因为结节阴性增加。与KRASG12D相比，KRASG12R肿瘤的远处复发率降低，生存率提高。为了了解其生物学基础，我们对20名患者进行了空间谱分析，并对100个肿瘤进行了大量RNA测序，发现KRASG12D肿瘤的致癌信号转导和上皮-间质转化（EMT）增强，而KRASG12R肿瘤的核因子κB（NF-κB）信号转导增强。对小鼠 KrasG12R PDAC 器官组织的正交研究显示，在正位模型中，迁移减少，存活率提高。因此，PDAC 中的 KRAS 改变与不同的表现形式、临床结果和生物学行为有关，突显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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.