A novel statistical feature selection framework for biomarker discovery and cancer classification via multiomics...

Early cancer diagnosis is essential for improving prognosis and guiding treatment. However, the high dimensionality and complexity of omics data present major challenges. Computational approaches that extract stable biomarkers and enable reliable classification across cancer types and stages are needed.

A novel feature selection method, sDCFE (synergistic Discriminative Cluster-based Feature Extraction), was developed by extending Fisher-like variance analysis with a median absolute deviation (MAD) regularization term and a cluster separation component to enhance robustness and interpretability. Features selected by sDCFE were compared with those obtained from XGBoost, and the intersected set of 82 genes was evaluated through functional enrichment (KEGG, Reactome, GO BP), survival analysis (Kaplan-Meier, Cox regression), and biomarker novelty assessment against six external resources. Hybrid classification models integrating XGBoost, sDCFE, and deep learning were applied to pancancer classification, and the framework was further extended to lung squamous cell carcinoma (LUSC) staging using RNA-seq and methylation data.

The overlap between sDCFE and XGBoost yielded 82 candidate biomarkers enriched in cancer-related pathways, including cell cycle regulation, immune signalling, and DNA repair. Novelty assessment stratified these genes into established, emerging, and novel categories. Six genes-HFE2, LOC339674, SERINC2, SFTA3, SOX2OT, and ACPP-emerged as the most promising candidates, supported by enrichment and survival associations across multiple cancers. The hybrid model achieved near-perfect pancancer classification on TCGA (accuracy = 99.3%, MCC = 0.992, AUC = 1.0) and demonstrated strong generalizability on PCAWG (accuracy = 94%, MCC = 0.929, AUC = 0.997). In the LUSC staging task, multiomics integration improved classification performance: the CNN-based model reached 84% accuracy, while logistic regression applied to sDCFE-ranked features achieved 88.5% accuracy with superior calibration, highlighting the robustness of the selected features.

sDCFE provides a principled extension of Fisher-like methods, enabling stable and interpretable biomarker selection. When combined with XGBoost and deep learning, the framework achieves highly accurate and biologically grounded cancer classification across both cancer types and stages. The identification of novel and prognostic biomarkers, including HFE2, LOC339674, SERINC2, SFTA3, SOX2OT, and ACPP, underscores its translational potential. These results position the framework as a promising precision oncology tool to support early diagnosis, risk stratification, and treatment decision-making.