Multi-Omics Analysis of CDKN2A (p16INK4a) in Cervical Carcinoma in the Context of Human Papillomavirus and in Endometrial Carcinoma

TL;DR

This study explores the role of CDKN2A in cervical and endometrial cancers, showing it is a strong diagnostic marker for cervical cancer and may help in endometrial cancer diagnosis.

Contribution

The study provides new insights into CDKN2A's diagnostic and prognostic roles in HPV-related and HPV-independent gynecologic cancers using multi-omics data.

Findings

CDKN2A shows excellent tumor–normal discrimination in cervical cancer (AUC = 0.982).

CDKN2A has moderate discriminatory ability in endometrial cancer (AUC = 0.761).

CDKN2A expression correlates with immune infiltration in a tumor-type-specific manner.

Abstract

Background: CDKN2A (p16^INK4a^) is integral to the regulation of the RB–E2F cell-cycle checkpoint and is widely acknowledged as a surrogate marker for high-risk human papillomavirus (HPV)-related cervical neoplasia. Nevertheless, its diagnostic and prognostic significance in uterine corpus endometrial carcinoma (UCEC), a predominantly HPV-independent malignancy, remains inadequately characterized. This study utilized an integrated multi-omics approach to examine CDKN2A dysregulation in cervical squamous cell carcinoma (CESC) and UCEC. Methods: Pan-cancer and tumor–normal differential expression analyses were performed using TIMER2.0 and GEPIA2 (TCGA/GTEx). Clinicopathological correlations were assessed with UALCAN. Protein expression patterns were analyzed using immunohistochemistry data from the Human Protein Atlas (HPA). Prognostic significance and immune-infiltration associations were evaluated using TCGA survival data and TIMER modules. Independent transcriptomic validation and diagnostic classification performance were assessed using GEO datasets GSE9750 (CESC) and GSE63678 (UCEC), including ROC-AUC analysis with cross-validation. Results: Integrated analyses revealed elevated CDKN2A expression in both CESC and UCEC across multiple transcriptomic cohorts, with pronounced tumor-specific protein expression on immunohistochemistry. TCGA-only tumor–normal RNA comparisons were non-significant, likely due to limited normal sample representation. In independent GEO cohorts, CDKN2A exhibited excellent tumor–normal discrimination in CESC (AUC = 0.982) and moderate discrimination in UCEC (AUC = 0.761). Survival analysis indicated tumor-specific patterns, with limited prognostic stratification in CESC and context-dependent associations in UCEC. Immune-infiltration analysis suggested tumor-type-specific interactions between CDKN2A expression and immune cell subsets. Conclusions: CDKN2A exhibits strong diagnostic performance in HPV-associated cervical cancer and moderate, cohort-dependent discriminatory ability in endometrial carcinoma. These findings reinforce its established diagnostic role in CESC and propose adjunctive utility in UCEC, underscoring the importance of tumor-contextual interpretation of CDKN2A expression in gynecologic malignancies.

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