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

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Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer
Cancer Cell ( IF 48.8 ) Pub Date : 2024-08-29 , DOI: 10.1016/j.ccell.2024.08.002
Caitlin A McIntyre ₁ , Adrien Grimont ₂ , Jiwoon Park ₃ , Yinuo Meng ₄ , Whitney J Sisso ₄ , Kenneth Seier ₅ , Gun Ho Jang ₆ , Henry Walch ₇ , Victoria G Aveson ₂ , David J Falvo ₂ , William B Fall ₄ , Christopher W Chan ₂ , Andrew Wenger ₈ , Brett L Ecker ₉ , Alessandra Pulvirenti ₁₀ , Rebecca Gelfer ₁₁ , Maria Paz Zafra ₁₂ , Nikolaus Schultz ₇ , Wungki Park ₁₃ , Eileen M O'Reilly ₁₃ , Shauna L Houlihan ₁₄ , Alicia Alonso ₁₂ , Erika Hissong ₁₅ , George M Church ₁₆ , Christopher E Mason ₁₇ , Despina Siolas ₈ , Faiyaz Notta ₆ , Mithat Gonen ₅ , Lukas E Dow ₈ , William R Jarnagin ₁₈ , Rohit Chandwani ₁₉

Affiliation

Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Marie-Josee and Henry R Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Pathology, Weill Cornell Medicine, New York, NY, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA.
Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.

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.

中文翻译：

人胰腺癌中特异性 KRAS 突变体的不同临床结局和生物学特征

胰腺导管腺癌（PDAC）中的 KRAS 突变被认为在致癌性方面有所不同，但尚未深入探讨其对人类患者的影响。我们检查了 1,360 例连续接受手术切除的 PDAC 患者，发现KRASG12R突变在早期（I 期）疾病中富集，这不是由于肿瘤较小，而是淋巴结阴性增加。与 KRASG12D 相比，KRASG12R 肿瘤与远处复发减少和生存率提高有关。为了了解生物学基础，我们对 20 名患者进行了空间分析和 100 名肿瘤的批量 RNA 测序，发现 KRASG12D 中致癌信号和上皮间质转化（EMT）增强，KRASG12R 例肿瘤中核因子 κB （NF-κB）信号增加。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和阐明突变特异性 PDAC 生物学的重要性。

更新日期：2024-08-29

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