PO.BCS01.01 · 生物信息与计算

PER3-RORB轴定义了一种与头颈部鳞状细胞癌生存改善相关的肿瘤抑制性昼夜节律状态

The PER3-RORB axis defines a tumor-suppressive circadian state associated with improved survival in head and neck squamous cell carcinoma

编号 49 展板 11 时间 4/19 02:00–05:00 区域 Section 3 主讲 Harold Nathan Tan, MD

分会场 Application of Bioinformatics to Cancer Biology 1

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作者与单位 Authors & Affiliations

Harold Nathan Tan, Oriol Mirallas, Paul Selvadurai, Michael Wotman, Luana Sousa, Neal Akhave, Khaled Sanber, Renata Ferrarotto, George R. Blumenschein, Maura L. Gillison, Faye M. Johnson, Timothy A. Yap

The University of Texas MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

背景：昼夜节律钟支配DNA修复、细胞周期进展、代谢和应激反应。昼夜节律紊乱已与肿瘤进展和治疗抵抗相关联，然而影响头颈部鳞状细胞癌（HNSCC）预后的节律钟组分仍未明确。我们试图表征HNSCC中的昼夜节律失调，并鉴定能够预测总生存期（OS）的昼夜节律特征。方法：使用一个昼夜节律基因面板对来自TCGA-HNSCC（n=565）的RNA-seq、临床和生存数据进行了分析，该面板包含核心正向调节因子（BMAL1、CLOCK、NPAS2、RORA、RORB、RORC）和负向调节因子（PER1/2/3、CRY1/2、NR1D1/2）。将Log₂归一化表达按每个基因进行z标准化，并将复合的正向臂和负向臂评分生成为各面板内的平均标准化表达。使用时间依赖性ROC曲线和多变量Cox模型评估预后性能。使用节律钟相干性破坏（ΔCCD）指标评估昼夜节律网络的完整性，在1,000次置换中将肿瘤中的节律钟基因相关结构与GTEx食管黏膜参考进行比较。使用limma的经验贝叶斯调节模型评估昼夜节律定义亚组之间的差异表达。结果：昼夜节律基因表达在不同原发部位和AJCC分期之间呈异质性，表明昼夜节律紊乱独立于临床因素。高RORB（HR = 0.75，p = 0.015）和高PER3（HR = 0.88，p = 0.05）与死亡率降低相关。在ROC分析中，PER3和RORB单独显示出适度的预后区分能力（3/5年时AUC分别为0.39/0.43和0.41/0.47）。相比之下，PER3-RORB复合评分（0.52/0.56）优于所有其他昼夜节律指标。节律钟相干性分析表明，PER3-RORB高表达肿瘤中保留了昼夜节律相关结构（CCD = 0.44），而PER3-RORB低表达肿瘤中则出现显著破坏（CCD = 0.74），产生的ΔCCD为0.31。没有任何置换重复超过该值（经验p < 0.001），表明与PER3-RORB缺失相关的网络崩溃高度非随机。PER3-RORB高表达肿瘤显示出NPAS2、代谢和应激反应基因（DHCR24、ABCA1、LRP1、ATP6V1A）的协调上调以及线粒体组分（NDUFB6）的调节，将这一轴与代谢和应激适应程序相联系。结论：PER3-RORB定义了一种与HNSCC生存改善相关、在生物学上具有相干性的昼夜节律状态。虽然这些发现支持PER3-RORB的肿瘤抑制作用，但仍需要独立的外部验证来确认其稳健性和临床普适性。这项工作凸显了昼夜节律调控作为肿瘤行为的机制性修饰因子，以及作为生物标志物开发的一个有前景的方向。

查看英文原文 English abstract

Background: The circadian clock governs DNA repair, cell-cycle progression, metabolism, and stress responses. Circadian disruption has been linked to tumor progression and therapy resistance, yet the clock components influencing prognosis in head and neck squamous cell carcinoma (HNSCC) remain undefined. We sought to characterize circadian dysregulation in HNSCC and identify circadian signatures that predict overall survival (OS). Methods: RNA-seq, clinical, and survival data from TCGA-HNSCC (n=565) were analyzed using a circadian gene panel comprising core positive regulators (BMAL1, CLOCK, NPAS2, RORA, RORB, RORC) and negative regulators (PER1/2/3, CRY1/2, NR1D1/2). Log₂-normalized expression was z-standardized per gene, and composite positive- and negative-arm scores were generated as mean standardized expression within each panel. Prognostic performance was evaluated using time-dependent ROC curves and multivariable Cox models. Circadian network integrity was assessed using the clock coherence disruption (ΔCCD) metric, comparing clock-gene correlation structure in tumors against a GTEx esophageal mucosa reference across 1,000 permutations. Differential expression between circadian-defined subgroups was evaluated with limma's empirical Bayes-moderated models. Results: Circadian gene expression was heterogeneous across primary sites and AJCC stages, indicating circadian disruption independent of clinical factors. High RORB (HR= 0.75, p=0.015), and PER3 (HR=0.88, p=0.05) were associated with reduced mortality. In ROC analysis, PER3 and RORB showed modest prognostic discrimination individually (AUC 0.39/0.43 and 0.41/0.47 at 3/5 years, respectively). In contrast, the PER3-RORB composite score (0.52/0.56) outperformed all other circadian metrics. Clock coherence analysis demonstrated preserved circadian correlation structure in PER3-RORB-High tumors (CCD = 0.44) and marked disruption in PER3-RORB-Low tumors (CCD = 0.74), yielding a ΔCCD of 0.31. No permutation replicate exceeded this value (empirical p < 0.001), indicating highly non-random network breakdown associated with PER3-RORB loss. PER3-RORB-high tumors showed coordinated upregulation of NPAS2, metabolic and stress-response genes (DHCR24, ABCA1, LRP1, ATP6V1A) and modulation of mitochondrial components (NDUFB6), linking this axis to metabolic and stress adaptation programs. Conclusion: PER3-RORB defines a biologically coherent circadian state linked to improved survival in HNSCC. While these findings support a tumor-suppressive role for PER3-RORB, independent external validation is required to confirm robustness and clinical generalizability. This work highlights circadian regulation as a mechanistic modifier of tumor behavior and a promising avenue for biomarker development.

利益披露 Disclosure

H. Tan, None. O. Mirallas, Merck Other, Writing aid. Roche Other, writing aid. Almirall Travel. Kyowa Kirin Travel. Recordati Travel. P. Selvadurai, None.. M. Wotman, None. L. Sousa, Coherus BioSciences Consulting or Advisory Role. Agenus (Inst) Other, Research Funding. Regeneron (Inst) Other, Research Funding. Dava Oncology Travel. N. Akhave, Aveo Pharmaceuticals ). Innocare Pharma ). Bicara Therapeutics ). Pfizer/Genmab ). Genmab/Pfizer. Consulting fees. K. Sanber, None. R. Ferrarotto, Answers in CME Other, Consulting or Advisory Role. Bicara Therapeutics Travel, Other, Consulting or Advisory Role. Coherus Biosciences Other, Consulting or Advisory Role. Eisai Other, Consulting or Advisory Role. Labcorp Drug Development Other, Consulting or Advisory Role. Raptor Pharmaceuticals Other, Consulting or Advisory Role. Regeneron Other, Consulting or Advisory Role. Rgenta Other, Consulting or Advisory Role. Gilead Sciences Other, Research Funding. ISA Pharmaceuticals Other, Research Funding. Merck Serono Other, Research Funding. Pfizer/EMD Serono Other, Research Funding. Remix Therapeutics Other, Research Funding. Seagen Other, Research funding. Viracta Therapeutics Other, Research funding. UpToDate Other, Royalties on UpToDate chapter on olfactory neuroblastoma, ~ 300 dollars per year. G. R. Blumenschein, Janssen (I) Employment. Johnson and Johnson (I) Employment. Virogin Biotech Stock. Bristol Myers Squibb Other, Consulting or Advisory Role. Bayer Other, Consulting or Advisory Role. Celgene Other, Consulting or Advisory Role. Clovis Oncology Other, Consulting or Advisory Role. AbbVie Other, Consulting or Advisory Role. ARIA Other, Consulting or Advisory Role. M. L. Gillison, Abbvie ), Other, Consulting or Advisory Role. ; Adaptimmune Other, Consulting or Advisory Role. Aptitude Health Other, Consulting or Advisory Role. Axiom Biotechnologies Other, Consulting or Advisory Role. Bayer Other, Consulting or Advisory Role. Bicara Therapeutics Other, Consulting or Advisory Role. BioNTech ), Other, Consulting or Advisory Role. Boxer Capital Other, Consulting or Advisory Role. Brightly Network Other, Consulting or Advisory Role. Bristol-Myers Squibb ), Other, Consulting or Advisory Role. Caladrius Biosciences Other, Consulting or Advisory Role. Coherus Biosciences Other, Consulting or Advisory Role. Debiopharm Group Other, Consulting or Advisory Role. Eisai Other, Consulting or Advisory Role. EMD Serono Other, Consulting or Advisory Role. Merck ), Other, Consulting or Advisory Role. Exelixis Other, Consulting or Advisory Role. Gilead Sciences ), Other, Consulting or Advisory Role. Pfizer Other, Consulting or Advisory Role. Roche ). F. M. Johnson, Takeda Pharmaceuticals ). T. A. Yap, Acrivon ), Other, Consultancy. Artios ), Other, Consultancy. AstraZeneca ), Other, Consultancy. Bayer Other, Consultancy. Beigene ), Other, Consultancy. BioNTech ). Vivace ). Bristol Myers Squibb ), Other, Consultancy. Boundless Bio ). Sanofi ), Other, Consultancy. Repare ), Other, Consultancy. Regeneron ). Eli Lilly ). EMD Serono ), Other, Consultancy. GlaxoSmithKline ), Other, Consultancy. Genentech ). Merck ), Other, Consultancy. Mirati ). , Novartis ). Pfizer Other, Consultancy.

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