PO.BCS01.01 · 生物信息与计算
The PER3-RORB axis defines a tumor-suppressive circadian state associated with improved survival in head and neck squamous cell carcinoma
作者与单位
摘要 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.