PO.CH02.01 · 化学

铂敏感与铂耐药高级别浆液性卵巢癌之间差异蛋白表达的蛋白质组学分析

A proteomic analysis of differential protein expression between platinum-sensitive and platinum-resistant high grade serous ovarian cancer

编号 7683 展板 7 时间 4/22 09:00–12:00 区域 Section 39 主讲 Nujsaubnusi Vue, MD

分会场 Proteomics: Biomarker Discovery and Signaling Networks

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作者与单位 Authors & Affiliations

Nujsaubnusi Cassandra Vue¹, Kyla Frenia², Xi Peng³, Eirwen Miller¹, John Nakayama¹, Sharon Liang¹, Sarah Crafton¹, Alyssa Wield¹, Christopher Morse¹, Thomas Krivak¹, Qiangmin Zheng³, Kunhong Xiao³

¹Western Pennsylvania Hospital, Pittsburgh, PA,²University of Pittsburgh, Pittsburgh, PA,³Allegheny Health Network, Pittsburgh, PA

摘要 Abstract

中文摘要

引言：卵巢癌是最致命的妇科恶性肿瘤。铂类为基础的治疗是治疗的主流，有70%的治疗敏感性可能。对铂类治疗的耐药是晚期卵巢癌死亡的主要原因。使用蛋白质组学评估卵巢癌铂耐药的研究有限。本研究旨在对铂敏感（PS）与铂耐药（PR）的高级别浆液性卵巢癌（HGSOC）肿瘤的初治组织进行蛋白质组学评估。方法：分析了从63例HGSOC患者收集的福尔马林固定石蜡包埋（FFPE）肿瘤组织，包括40例PS和23例PR。铂敏感性定义为治疗6个月后疾病有反应且无复发证据。样本使用高通量液相色谱-串联质谱（LC-MS/MS）方案进行分析。进行差异表达（DE）分析以识别区分两组的蛋白。采用无监督机器学习技术，如最小绝对收缩和选择算子（LASSO）回归分析、线性判别分析（LDA）和加权基因共表达网络分析（WGCNA），以创建PS和PR之间的差异表达蛋白谱。结果：在识别的4048种蛋白中，1604种符合进一步分析的质量阈值，出现在>50%的样本中。37种蛋白显著差异表达，其中4种在PS中上调，33种在PR中上调。通过LASSO回归分析，额外识别出61种DE蛋白。LDA揭示7种蛋白（DPM1、INF2、ISYNA1、RBM12B、ATP5F1C、GNL1、UBA7）具有预测潜力，敏感性85%，特异性100%。功能富集分析提示与RNA结合、表观遗传调控、剪接体活性、谷胱甘肽代谢和代谢重编程相关的通路参与铂敏感性。结论：通过结合传统统计学和无监督机器学习，本研究生成了一份DE蛋白清单，并促成了一个7蛋白组合，可用于进一步研究和理解铂敏感性和耐药性背后的复杂肿瘤动态。

查看英文原文 English abstract

Introduction: Ovarian cancer is the most lethal gynecologic malignancy. Platinum-based therapy is the mainstay of treatment, with 70% chance of treatment sensitivity. Resistance to platinum therapy is the leading cause of mortality in advanced ovarian cancer. There are limited studies using proteomics to evaluate platinum resistance in ovarian cancer. This study aims to perform proteomic evaluation of treatment naive tissue from high grade serous ovarian cancer (HGSOC) tumors that are platinum-sensitive (PS) versus resistant (PR). Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue collected from 63 patients with HGSOC were analyzed, including 40 PS & 23 PR. Platinum sensitivity was defined as disease response without evidence of recurrence after 6 months of treatment. Samples were analyzed using a high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol. Differential expression (DE) analysis was performed to identify proteins distinguishing between the two groups. Unsupervised machine learning techniques such as least absolute shrinkage and selection operator (LASSO) regression analysis, linear discriminant analysis (LDA), and weighted gene co-expression network analysis (WCGNA) were employed to create a differentially expressed protein profile between PS and PR. Results: Among 4048 proteins identified, 1,604 met quality thresholds for further analysis, appearing in >50% of samples. Thirty-seven proteins were significantly differentially expressed with four upregulated in PS and 33 upregulated in PR. With LASSO regression analysis, an additional 61 DE proteins were identified. LDA revealed 7 proteins (DPM1, INF2, ISYNA1, RBM12B, ATP5F1C, GNL1, UBA7) to have a predictive potential with 85% sensitivity and 100% specificity. Functional enrichment analysis implicated pathways related to RNA binding, epigenetic regulation, spliceosome activity, glutathione metabolism, and metabolic reprogramming in platinum sensitivity. Conclusion: With the combination of traditional statistics and unsupervised machine learning, this study generated a list of DE proteins and facilitated a 7-protein panel that can be used to further investigate and understand the complex tumor dynamics behind platinum sensitivity and resistance.

利益披露 Disclosure

N. C. Vue, None.. K. Frenia, None.. X. Peng, None.. E. Miller, None. J. Nakayama, AstraZeneca Other, consulting fees and payment. Abbvie Other, consulting fees. Myriad Other, consulting fees and payment. Merck Other, Payment. Eisai Payment. S. Liang, None. S. Crafton, Pfizer g., Board of Directors, non-salaried role), consulting or advisory board. Karyopharm g., Board of Directors, non-salaried role), consulting or advisory board. GSK g., Board of Directors, non-salaried role), consulting or advisory board. Medtronic g., Board of Directors, non-salaried role), consulting or advisory board. A. Wield, None. C. Morse, MJH Lifesciences Honoraria. Topline Bio Honoraria. T. Krivak, Astra Zeneca Other, consulting fees, payments, and honoraria. Immunogen Other, consulting fees, payments, and honoraria. GSK Other, consulting fees, payments, and honoraria. Myriad Other, consulting fees, payments, and honoraria. Q. Zheng, None.. K. Xiao, None.

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