Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

Abstract

Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers.

Keywords: TCGA; cancer metabolism; cellular respiration; glycolysis; head and neck cancer; human papillomavirus.

Figure 1

Genes differentially expressed between HPV-positive (HPV+) head and neck squamous cell carcinomas (HNSCC), HPV-negative (HPV-) HNSCC, and normal control tissues by metabolic pathway. The y-axis reflects the proportion of genes that are up or downregulated in a given pathway comparison. For example, the positive fraction of genes reflects the proportion of genes upregulated in the first group (e.g., HPV+) when compared to the second group (e.g., HPV-). The negative fraction of genes reflects the proportion of genes downregulated in the same comparison. Blue = HPV+ tissue vs HPV- tissue comparison; Red = HPV+ tissue vs normal control tissue comparison; Green = HPV- tissue vs normal control tissue comparison. Numbers in brackets denote total number of genes analyzed from each pathway. Abbreviations: TCA, tricarboxylic acid cycle; Resp., respiratory; F.A., fatty acid; PPP, pentose phosphate pathway.

Figure 2

Low expression of SDHC is associated with favorable survival outcomes in HPV+ HNSCC. (A) Transcript levels of SDHC across all HNSCC tissues samples and normal control tissues. Bracketed numbers refer to the sample size of each group. Overall five-year survival outcomes in (B) HPV+ HNSCC and (C) HPV- HNSCC patients dichotomized by SDHC expression. p = Two-sided log-rank test, q = Benjamini-Hochberg FDR method. Gray = low transcript expression, Black = high transcript expression. * p ≤ 0.05, ** p ≤ 0.01, ns (not significant).

Figure 3

Low expression of three mitochondrial respiration complex IV genes in HPV+ HNSCC is associated with improved survival. Expression of (A) COX7A1, (D) COX16, and (G) COX17 in HNSCC tissues samples and normal control tissues. Overall 5-year survival outcomes in HPV+ HNSCC patients and HPV- HNSCC dichotomized by median (B,C) COX7A1 expression, (E,F) COX16 expression, and (H,I) COX17 expression. p = Two-sided log-rank test, q = Benjamini-Hochberg FDR method. Gray = low transcript expression, Black = high transcript expression. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001, ns (not significant).

Figure 4

Low expression of ELOVL6, GOT2 and SLC16A2 is associated with improved patient survival in HPV+ HNSCC. Expression of (A) ELOVL6, (D) GOT2, and (G) SLC16A2 in HPV+, HPV- HNSCC tissue samples and normal control tissues. Overall five-year survival outcomes in HPV+ HNSCC and HPV- HNSCC patients dichotomized by median (B,C) ELOVL6 expression, (E,F) GOT2 expression, and (H,I) SLC16A2 expression. p = Two-sided log-rank test and q = Benjamini-Hochberg FDR method. Gray = low transcript expression, Black = high transcript expression. **** p ≤ 0.0001, ns (not significant).

Figure 5

HPV+ HNSCC patient survival stratified by double low or double high expression of survival-associated metabolic genes. (A) COX16 and COX17, (B) COX16 and SLC16A2, (C) COX17 and SLC16A2. Comparisons made with a two-sided log-rank test. Gray = low transcript expression, Black = high transcript expression. Bracketed value indicates number of HPV+ HNSCCs with double high or double low expression for genes of interest.