PO.CL01.16 · 临床研究

多样性对胰腺导管腺癌患者骨骼肌转录异质性的影响

The impact of diversity on transcriptional heterogeneity of skeletal muscle from pancreatic ductal adenocarcinoma patients

编号 3944 展板 19 时间 4/20 02:00–05:00 区域 Section 48 主讲 Praveen Bhoopathi, PhD

分会场 Prognostic Biomarkers 2

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作者与单位 Authors & Affiliations

Praveen Bhoopathi¹, Vignesh Vudatha², Arunima Punjala², Vashti Bandy², Anna Gibson², Dongyu Zhang², Katarzyna M. Tyc³, Mikhail Dozmorov³, Jeremy Ducharme⁴, Martin Schonk⁴, Brittney Poole⁴, Sarah Judge⁴, Leopoldo Fernandez¹, Andrew R. Judge⁴, Jose G. Trevino¹

¹Surgery (Surgical Oncology) and Massey Comprehensive Cancer center, Virginia Commonwealth University - VCU, Richmond, VA,²Surgery (Surgical Oncology), Virginia Commonwealth University - VCU, Richmond, VA,³Department of Biostatistics, Virginia Commonwealth University - VCU, Richmond, VA,⁴Department of Physical Therapy and Myology Institute, University of Florida, Gainesville, FL

摘要 Abstract

中文摘要

目的：恶病质在胰腺导管腺癌（PDAC）患者的发病率和死亡率中起主要作用。本研究的目的是从手术切除的PDAC患者中阐明肌肉中促成癌性恶病质的分子通路。方法：在PDAC手术切除时，锐性分离腹直肌并立即速冻用于RNA-seq。采用标准方案从冷冻组织中提取总RNA，并在文库制备前确认RNA完整性。随后将所得高质量RNA用于RNA测序（RNA-seq）分析，以发现独特的变异体；此外，基于约13,007个频繁表达转录本的核心转录特征，评估了差异转录本表达。采用KEGG通路和MSigDB基因集（Hallmark、Curated、GO特征）进行基因集富集分析（GSEA），该分析同时利用差异表达基因（DEGs）的倍数变化和排序来发现富集的生物学通路。结果：发现肌肉组织中显著的转录组变异与患者种族和生存相关。比较黑人（Black）和白人（White）患者的MSigDB基因集显示，非裔美国人（AA）队列在与炎症、心肌病和肌肉萎缩/蛋白质稳态相关的通路中激活程度更高。通过将这些通路与显著DEGs交叉比对，发现了三个重叠基因：CYP4B1、DDIT4（在AA中上调，与肌肉萎缩/恶病质显著相关）和GINS1（在AA中下调，与增殖相关）。此外，包括生理学上重要的基因ADAM28、SENCR和MEG8（与肌肉分化和肿瘤进展相关）在内的八个基因被发现与总生存显著相关。结论：肌肉组织的RNA-seq和GSEA为PDAC相关的全身分子改变提供了关键见解。所识别的通路和基因，尤其是那些表现出种族和生存相关异质性的基因（如DDIT4、GINS1），代表了解决PDAC中肌肉功能障碍和恶病质的潜在生物标志物和治疗靶点。

查看英文原文 English abstract

Objective: Cachexia plays a major role in the morbidity and mortality of pancreatic ductal adenocarcinoma (PDAC) patients. The objective of this study is to delineate the molecular pathways of muscle that contribute to cancer cachexia from surgically resected PDAC patients. Methods: At surgical resection for PDAC, rectus abdominus muscle was sharply divided and shock frozen immediately for RNA-seq. Total RNA was extracted from the frozen tissue using standard protocols, and RNA integrity was confirmed prior to library preparation. The resulting high-quality RNA was then used for RNA sequencing (RNA-seq) analysis to find distinct variants in addition to a core transcriptional signature of roughly 13,007 frequently expressed transcripts, differential transcript expression was evaluated. KEGG pathways and MSigDB collections (Hallmark, Curated, GO signatures) were used in Gene Set Enrichment Analysis (GSEA), which uses both fold change and ranking of differentially expressed genes (DEGs) to find enriched biological pathways. Results: Significant transcriptome variations in muscle tissue were found to be associated with patient race and survival. MSigDB gene sets comparing Black and White ) patients revealed that the AA cohort had higher activation of pathways linked to inflammation, cardiomyopathy, and muscle atrophy/proteostasis. Three overlapping genes were found by cross-referencing these pathways with significant DEGs: CYP4B1, DDIT4 (upregulated in AA, significantly related with muscular atrophy/cachexia), and GINS1 (downregulated in AA, associated with proliferation). Additionally, eight genes including the physiologically significant genes ADAM28, SENCR, and MEG8 (related with muscle differentiation and tumor progression) were found to be substantially associated with overall survival. Conclusion: RNA-seq and GSEA of muscle tissue provide critical insights into the systemic molecular alterations associated with PDAC. The identified pathways and genes, particularly those demonstrating racial and survival-associated heterogeneity (e.g., DDIT4, GINS1), represent potential biomarkers and therapeutic targets for addressing muscle dysfunction and cachexia in PDAC.

利益披露 Disclosure

P. Bhoopathi, None.. V. Vudatha, None.. A. Punjala, None.. V. Bandy, None.. A. Gibson, None.. D. Zhang, None.. K. M. Tyc, None.. M. Dozmorov, None.. J. Ducharme, None.. M. Schonk, None.. B. Poole, None.. S. Judge, None.. L. Fernandez, None.. A. R. Judge, None.. J. G. Trevino, None.

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