Increased CDKN2A expression correlates with resistance to platinum-based therapy and decreased infiltration of B lymphocytes in colon adenocarcinoma.

Abstract

Background: Cuproptosis-related gene CDKN2A is involved in the development and progression of various solid tumors. However, the potential involvement of CDKN2A in colon adenocarcinoma (COAD) remains unexplored.

Methods: The expression profiles of cuproptosis-related genes in COAD and their relationships with survival prognosis were analyzed using TCGA and GEO bulk RNA-sequencing datasets. Subsequently, enrichment analysis, genomic mutation analysis, drug sensitivity analysis, and immune infiltration analysis were conducted to assess the significance of CDKN2A in COAD. Using a single-cell RNA-sequencing dataset, we investigated the intercellular communication networks among B lymphocytes according to CDKN2A expression. Furthermore, the potential roles of CDKN2A in COAD were validated through a series of in vitro experiments.

Results: CDKN2A was highly expressed in COAD, contributing to platinum resistance through its association with extracellular matrix organization and DNA adduct chemical carcinogenesis. It correlated with the Wnt and Hippo signaling pathway, poor prognosis, and reduced B lymphocyte infiltration, but was not a major oncogenic driver in COAD. Elevated CDKN2A altered the communication patterns between non-switched memory B cells and switched memory B cells. Notably, small interfering RNA-mediated knockdown of CDKN2A in COAD inhibited glycolysis, promoted cuproptosis, and suppressed tumor proliferation, invasion and migration.

Conclusion: Our study demonstrated that the cuproptosis-related gene CDKN2A is a promising prognostic biomarker in COAD and may potentially guide the personalized chemotherapy regimens for COAD patients.