Two Molecular Subgroups Predict Most Recurrences in Advanced Laryngeal Squamous Cell Carcinoma
Todor M Popov1, Gergana S Stancheva2, Veronika Petkova2
1Department of ENT, Medical University - Sofia, Sofia, Bulgaria.
Cancer Research Communications
|December 8, 2025
Summary
Vascular Endothelial Growth Factor-A (VEGF-A) predicts recurrence in laryngeal cancer depth, not surface. A high-risk miRNA signature also identifies patients with worse outcomes, defining subgroups for risk stratification.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Research
Background:
- Inconsistent reports exist regarding Vascular Endothelial Growth Factor-A (VEGF-A) as a prognostic marker in laryngeal squamous cell carcinoma (LSCC).
- Intratumoral heterogeneity may explain these discrepancies.
- Identifying reliable prognostic markers is crucial for risk stratification in LSCC.
Purpose of the Study:
- To investigate if intratumoral heterogeneity influences VEGF-A's prognostic value in LSCC.
- To identify specific mRNA and miRNA expression phenotypes associated with LSCC recurrence.
- To define molecular subgroups that capture a significant proportion of recurrences.
Main Methods:
- Prospective cohort study of 60 T3/T4 LSCC patients undergoing primary laryngectomy.
- Sampling of four distinct regions per tumor: surface, depth, peritumoral mucosa, and normal mucosa.
- Quantification of hypoxia-inducible factor (HIF) 1α/2α/3α, VEGF-A, VEGFR1/2, and ETS-1 mRNA via qRT-PCR.
- Integrated miRNA profiling using microarray and qRT-PCR validation.
Main Results:
- Elevated VEGF-A at tumor depth significantly predicted recurrence (log-rank P = 0.0001), while surface VEGF-A did not (P = 0.170).
- VEGF-A levels were significantly higher at tumor depth compared to the surface (Wilcoxon P = 0.026).
- A subgroup with high depth VEGF-A and low HIF1α showed a 64% recurrence rate.
- An independent subgroup with high expression of miR-93-5p, miR-144-3p, and miR-210-3p also exhibited significantly worse outcomes.
- These two subgroups accounted for 76% of all recurrences and were largely non-overlapping.
Conclusions:
- The prognostic relevance of VEGF-A in LSCC is region-dependent, with meaningful value confined to tumor depth.
- A high-risk three-miRNA signature identifies a distinct subgroup with poor prognosis.
- These findings delineate two molecular subgroups capturing most recurrences and can inform sampling strategies and risk stratification in LSCC.
