Unraveling Differences in Molecular Mechanisms and Immunological Contrasts between Squamous Cell Carcinoma and Adenocarcinoma of the Cervix

Abstract

This study aims to refine our understanding of the inherent heterogeneity in cervical cancer by exploring differential gene expression profiles, immune cell infiltration dynamics, and implicated signaling pathways in the two predominant histological types of cervix carcinoma, Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). Targeted gene expression data that were previously generated from samples of primary cervical cancer were re-analyzed. The samples were grouped based on their histopathology, comparing SCC to ADC. Each tumor in the study was confirmed to be high risk human papilloma virus (hrHPV) positive. A total of 21 cervical cancer samples were included, with 11 cases of SCC and 10 of ADC. Data analysis revealed a total of 26 differentially expressed genes, with 19 genes being overexpressed in SCC compared to ADC (Benjamini-Hochberg (BH)-adjusted p-value < 0.05). Importantly, the immune checkpoint markers CD274 and CTLA4 demonstrated significantly higher expression in SCC compared to ADC. In addition, SCC showed a higher infiltration of immune cells, including B and T cells, and cytotoxic cells. Higher activation of a variety of pathways was found in SCC samples including cytotoxicity, interferon signaling, metabolic stress, lymphoid compartment, hypoxia, PI3k-AKT, hedgehog signaling and Notch signaling pathways. Our findings show distinctive gene expression patterns, signaling pathway activations, and trends in immune cell infiltration between SCC and ADC in cervical cancer. This study underscores the heterogeneity within primary cervical cancer, emphasizing the potential benefits of subdividing these tumours based on histological and molecular differences.

Keywords: adenocarcinoma; cervical cancer; immune cells; squamous cell carcinoma; targeted gene expression profiling.

Figure 1

Overview of the study and the findings. (A) Schematic representation of the study design [1]. (B) Volcano plot of the differentially expressed genes between Squamous Cell Carcinoma (SCC) and Adeno Cell Carcinoma (ADC). The dotted red line presents the BH-p-value < 0.05. The horizontal dotted lines present the Fold of Change (FOC) > 1. Every dot presents a measured gene, while the orange dots are DEG higher in SCC, green dots are DEG lower in SCC (BH, p-value < 0.05) and gray dots are not significantly different between the two groups. (C) Heat-map of the DEG genes that were filtered additionally by FOC > 1.

Figure 2

The immune landscape of cervical Squamous Cell Carcinoma (SCC) and Adeno Cell Carcinoma (ADC). (A) Bar plot of the p-values resulted from the comparison of immune cell infiltration scores. Yellow bars are for the significant scores and the blue bars are for the not significant scores. (B) Box plots for significantly abundant immune cells in SCC. (C) Box plots of the differentially expressed immune checkpoint targets. (* p-value < 0.05).

Figure 3

Pathway scores for Squamous Cell Carcinoma (SCC) and Adeno Cell Carcinoma (ADC). Bar plot of the p-values resulted from the (A) bar plot of the p-values resulted from the comparison of pathway scores. Yellow bars are for the significant scores and the blue bars are for the not significant scores. (B) Box plots for the following significant pathways: cytotoxicity, notch signaling, interferon signaling, autophagy, metabolic stress, lymphoid compartment, hypoxia, PI3K-Akt, and hedgehog signaling. (* p-value < 0.05).

Figure 4

Comparing the volcano plots of GSA for cytotoxicity, notch signaling, interferon signaling, autophagy, metabolic stress, lymphoid compartment, hypoxia signaling, PI3K-Akt, and hedgehog signaling pathways between SCC (orange dots) and ADC (green dots). The dashed red line shows significance level of p value.