Multi-omics characterization of prognostic signature and novel molecular subtypes associated with anoikis and in vitro validation of CDKN2A in thyroid carcinoma

Background

Anoikis plays a crucial role in thyroid carcinoma (THCA). Recent evidence has suggested CDKN2A as a key anoikis-related gene (ARG) associated with THCA. However, the multi-omics regulatory landscape of ARGs and their potential to define molecular subtypes with distinct therapeutic vulnerabilities remain unexplored.

Methods

We utilized multi-omics data from The Cancer Genome Atlas including transcriptomic, methylation, and miRNA profiles, to analyze ARG expression and survival outcomes in THCA patients. Single-cell sequencing and clustering analyses were conducted to identify distinct molecular subtypes. A risk scoring model was developed based on ARGs, and its predictive performance was validated. Drug vulnerability was assessed to determine the sensitivity of molecular subtypes to various therapies.

Results

Patients with THCA demonstrated a pronounced shift toward positive anoikis regulation compared with healthy controls. Integrated multi-omics analyses identified E2F1, LGALS3, CDKN2A, and LPAR1 as key prognostic genes. A risk score model incorporating these genes exhibited strong predictive accuracy, with a C-index of 0.85. Unsupervised clustering delineated two distinct molecular subtypes—Cluster 1 and Cluster 2—with Cluster 1 associated with enhanced inflammatory cell infiltration and superior overall survival. Drug sensitivity profiling further revealed differential responses to conventional chemotherapies and targeted therapies between the two subtypes. Functional validation established CDKN2A as a critical mediator of anoikis resistance and immune microenvironment modulation in THCA.

Conclusions

This study advances prior research by establishing the first multi-omics-driven molecular subtypes of THCA, and provides a comprehensive regulatory framework for anoikis in THCA. The identification of subtype-specific drug vulnerabilities and functional validation of CDKN2A's role in stromal crosstalk offer transformative insights for personalized therapy.