Significant association between host transcriptome‐derived HPV oncogene E6* influence score and carcinogenic pathways, tumor size, and survival in head and neck cancer

Abstract

Background Human papillomavirus (HPV) oncogenes E6, E7, and shorter isoforms of E6 (E6*) are known carcinogenic factors in head and neck squamous cell carcinoma (HNSCC). Little is known regarding E6* functions. Methods We analyzed RNA‐seq data from 68 HNSCC HPV type 16‐positive tumors to determine host genes and pathways associated with E6+E7 expression (E6E7) or the percent of full‐length E6 (E6%FL). Influence scores of E6E7 and E6%FL were used to test for associations with clinical variables. Results For E6E7, we recapitulated all major known affected pathways and revealed additional pathways. E6%FL was found to affect mitochondrial processes, and E6%FL influence score was significantly associated with overall survival and tumor size. Conclusions HPV E6E7 and E6* result in extensive, dose‐dependent compensatory effects and dysregulation of key cancer pathways. The switch from E6 to E6* promotes oxidative phosphorylation, larger tumor size, and worse prognosis, potentially serving as a prognostic factor for HPV‐positive HNSCC.

Association of human papillomavirus integration with better patient outcomes in oropharyngeal squamous cell carcinoma

“…E1 was the HPV gene most frequently involved in integration (40% of sites), which is in agreement with previous studies. 12,41 Even though there were a limited number of integration sites detected (n = 35), we were able to determine that integration events took place across 11 different chromosomes (chromosomes 1,2,3,4,6,7,8,9,13,14,17). Of the integration sites detected, only eight (23%) were within cellular genes.…”

“…We assessed the expression of alternate E6* transcripts; these transcripts are thought to contribute to a more aggressive phenotype, resulting in larger tumors and worse patient prognosis 17 . We found that the majority of samples expressed both E6FLE7 and alternate E6* transcripts with a few samples only expressing E6* transcripts.…”

“…E2 is frequently, but not always, disrupted as a result of integration, which results in increased E6/E7 due to the role of E2 as a negative transcriptional regulator 15 . Integration of HPV has also been reported to be associated with increased expression of shorter, spliced transcripts of E6 known as E6*I and E6*II, 16 which have been shown to be associated with dysregulation of key cancer pathways and worse outcomes for HPV + HNSCC patients 17 . Additionally, integration into cellular genes can lead to the generation of viral‐host fusion transcripts, and it has been reported that these transcripts may be more stable than episomally derived HPV transcripts that then allows for the HPV oncogenes to persist longer 18 .…”

“…15 Integration of HPV has also been reported to be associated with increased expression of shorter, spliced transcripts of E6 known as E6*I and E6*II, 16 which have been shown to be associated with dysregulation of key cancer pathways and worse outcomes for HPV + HNSCC patients. 17 Additionally, integration into cellular genes can lead to the generation of viral-host fusion transcripts, and it has been reported that these transcripts may be more stable than episomally derived HPV transcripts that then allows for the HPV oncogenes to persist longer. 18 Some have reported that E6/E7 levels are increased in HNSCC cell lines and tumors with integrated HPV, 19,20 but others have reported that this is not necessarily true in every case.…”

Identification of Expression Patterns and Potential Prognostic Significance of m5C-Related Regulators in Head and Neck Squamous Cell Carcinoma

“…Moreover, the enriched signaling cascade for the 359 upregulated and 366 downregulated genes identified by the analysis of the KEGG pathway was selected according to log 2 FC (p < 0.05). In the high-risk subgroup, the top-ranking terms were associated with "ribosome, " "oxidative phosphorylation, " "non-alcoholic fatty liver disease, " and "synaptic vesicle cycle, " and so on (p < 0.05); among them, "oxidative phosphorylation" was testified to be related to larger tumor size of HNSCC (Figure 8G) (42). Verification of the low-risk subgroup with KEGG analysis also revealed that "cell cycle" and "HTLV-infection" were linked with these genes (Figure 8H).…”