Abstract
Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients' response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of anatomical location by analyzing The Cancer Genome Atlas and Gene Expression Omnibus databases. In the present study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high- and low-risk groups in HPV-associated CC and HNC, identifying molecular biomarkers and pathways for risk stratification. Among the 174 identified DEGs, the expression of genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, and LAMC1) was increased in high-risk groups in both HPV-associated CC and HNC, while the expression of genes associated with T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) was decreased and vice versa. The individual genes showed significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations and distinct patterns of immune cell infiltration in tumor microenvironments. These results allowed us to identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical location. The identified targets were found to be selectively working in only HPV-associated cancers and not in HPV-negative cancers, indicating the possibility of selective targets governing HPV-infective tumor microenvironments.
Highlights
Human papillomavirus (HPV) is a small circular virus with approximately 8 kb of double-stranded DNA genome comprising the following three major functional regions: (i) an upstream regulatory region (URR) with transcription factor-binding sites controlling gene expression; (ii) an early region encoding six genes (E1, E2, E4, E5, E6, E7) having multiple functions including viral replication, and (iii) a late region encoding capsid proteins L1 and L2 that produce the virion by self-assembly [1,2]
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to select target genes that explain the molecular mechanisms among common differentially expressed genes (DEGs), and four upregulated genes (ITGA5, ITGB1, LAMB1, and LAMC1), and five downregulated genes (CD3D, CD3E, CD8B, LCK, and ZAP70) were selected (Fig. 2A–D, Tables 2 and 3)
High levels of gene expression of Intergrin alpha 5 (ITGA5), ITGB1, LAMB1, and LAMC1 were associated with a worse overall survival (OS), while low levels of gene expression of CD3D, CD3E, CD8B, LCK, and ZAP70 were associated with a worse OS of patients with HPV-related cancers (Fig. 3A,B)
Summary
Human papillomavirus (HPV) is a small circular virus with approximately 8 kb of double-stranded DNA genome comprising the following three major functional regions: (i) an upstream regulatory region (URR) with transcription factor-binding sites controlling gene expression; (ii) an early region encoding six genes (E1, E2, E4, E5, E6, E7) having multiple functions including viral replication, and (iii) a late region encoding capsid proteins L1 and L2 that produce the virion by self-assembly [1,2]. Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. We comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high- and low-risk groups in HPV-associated CC and HNC, identifying molecular biomarkers and pathways for risk stratification. Results: Among the 174 identified DEGs, the expression of genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, and LAMC1) was increased in high-risk groups in both HPV-associated CC and HNC, while the expression of genes associated with T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) was decreased and vice versa. Conclusions: These results allowed us to identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical location. The identified targets were found to be selectively working in only HPV-associated cancers and not in HPV-negative cancers, indicating the possibility of selective targets governing HPV-infective tumor microenvironments
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