PO.CL01.02 · 临床研究
细胞外囊泡相关的非经典 ORF 作为卵巢癌手术结局和化疗耐药的生物标志物
Extracellular vesicle-associated noncanonical ORFs as biomarkers of surgical outcome and chemoresistance in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤，复发和化疗耐药导致不良生存结局。除经典耐药机制外，基因组的大部分区域编码非经典开放阅读框（ncORF），产生短的、内在无序的蛋白质/肽（ncPR），标准蛋白质组学大多无法检测（“暗蛋白质组”）。新兴证据表明 ncPR 参与肿瘤可塑性、应激适应、细胞间通讯和药物耐药。它们在 HGSOC 化疗耐药中的作用以及包装进细胞外囊泡（EV）的情况仍未被探索。
方法：我们分析了来自 30 例患者原发肿瘤的 RNA-seq 数据集和来自 28 例患者的配对 EV RNA-seq。队列包括完全大体切除（CGR，n = 10）和新辅助化疗（NACT）后应答优异（NACT-ER，n = 9）或应答不良（NACT-PR，n = 9）的患者。使用非经典 ORF 数据库量化 ncORF 丰度，并评估其与临床结局的关联。
结果：原发肿瘤和 EV 显示出不同的 ncORF 生物型分布。表现出编码 ncORF 减少 17% 和内含子 ncORF 减少 10%（p < 0.0001），而假基因和 ncRNA 来源的 ncORF 及 3′UTR 来源的 ncORF 分别增加 64% 和 53%（p < 0.0001）。尽管数量较少，假基因来源的 ncORF 在 EV 中显示出比编码来源的 ncORF 更高的平均丰度。其丰度模式趋向于区分 CGR 与 NACT 患者（Fisher 精确检验 p = 0.004）以及 NACT-ER 与 NACT-PR（P = 0.08）。
结论：ncORF，尤其是假基因和 ncRNA 来源的，在 HGSOC 患者的 EV 中被选择性富集，提示其在细胞间通讯和治疗应答中的作用。这些发现凸显了 EV 相关的 ncORF 作为卵巢癌潜在生物标志物和治疗靶点的价值。
查看英文原文 English abstract
Background: High-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy, with recurrence and chemoresistance driving poor survival outcomes. Beyond canonical resistance mechanisms, large portions of the genome encode non-canonical open reading frames (ncORFs) that produce short, intrinsically disordered proteins/peptides (ncPRs), largely undetectable by standard proteomics (“dark proteome”). Emerging evidence implicates ncPRs in tumor plasticity, stress adaptation, intercellular communication, and drug resistance. Their role in HGSOC chemoresistance and packaging into extracellular vesicles (EVs) remain unexplored.
Methods: We analyzed RNA-seq datasets from primary tumors of 30 patients and matched EV RNA-seq from 28 patients. Cohorts included patients with complete gross resection (CGR, n = 10) and neoadjuvant chemotherapy (NACT) with excellent (NACT-ER, n = 9) or poor response (NACT-PR, n = 9). ncORF abundances were quantified using a non-canonical ORF database and associations with clinical outcomes were assessed.
Results: Primary tumors and EVs showed distinct ncORF biotype distributions. exhibited a 17% decrease in coding and 10% decrease in intronic ncORFs (p < 0.0001), with 64% and 53% increases in pseudogene- and ncRNA-derived ncORFs and 3′UTR-derived ncORFs, respectively (p < 0.0001). Although fewer in number, pseudogene-derived ncORFs showed higher mean abundance than coding-derived ncORFs in EVs. Their abundance patterns trended toward discriminating CGR versus NACT patients (Fishers' exact test p = 0.004) and NACT-ER vs NACT-PR (P = 0.08).
Conclusions: ncORFs, particularly pseudogene and ncRNA-derived, are selectively enriched in EVs from HGSOC patients, suggesting roles in intercellular communication and therapy response. These findings highlight EV-associated ncORFs as potential biomarkers and therapeutic targets in ovarian cancer.
利益披露 Disclosure
T. V. Karpinets, None..
X. Wu, None..
S. Corvigno, None..
A. Asare, None..
J. Celestino, None..
J. J. Cutrera, None..
P. T. Soliman, None.
S. N. Westin,
Astra Zeneca ), Other, Consulting.
AvengeBio ), Other.
Bayer ), Other, Consulting.
Bio-Path ).
Clovis Oncology/Pharm&, ), Other, Consulting.
Daiichi Sankyo ), Other, Consulting.
GSK ), Other, Consulting.
Loxo ), Other, Consulting.
Mereo ), Other, Consulting.
Nuvectis, ), Other, Consulting.
Pfizer ), Other, Consulting.
Roche/Genentech ), Other, Consulting.
Verastem ), Other, Consulting.
Zentalis ), Other, Consulting.
Jazz Pharmaceuticals ).
Novartis ).
AbbVie Other, Consulting.
Caris Other, Consulting.
Corcept Other, Consulting.
Eisai, Genmab, Gilead, Immunocore, ImmunoGen, Incyte, Lilly, Merck, NGM Bio, SeaGen, ZielBio Other, Consulting.
A. A. Jazaeri, None..
P. Futreal, None.
A. K. Sood,
Onxeo Other, Consulting.
StarPharma Other, Consulting.
Kaida Other, Consulting.
Foundation Medicine Other, Consulting.
Advenchen Other, DSMB.
Mural Oncology Other, DSMB.
Pfizer ).
S. Lee, None.