A Network Landscape of HPVOPC Reveals Methylation Alterations as Significant Drivers of Gene Expression via an Immune-Mediated GPCR Signal.
Jesse R QualliotineTakuya NakagawaSara Brin RosenthalSayed SadatCarmen Ballesteros-MerinoGuorong XuAdam MarkArt NasamranJ Silvio GutkindKathleen M FischTheresa W GuoBernard A FoxZubair KhanAlfredo A MolinoloJoseph A CalifanoPublished in: Cancers (2023)
HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16-human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor-immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.
Keyphrases
- dna methylation
- genome wide
- gene expression
- copy number
- network analysis
- cell migration
- mitochondrial dna
- endothelial cells
- high grade
- squamous cell carcinoma
- single cell
- risk factors
- protein protein
- papillary thyroid
- transcription factor
- signaling pathway
- type diabetes
- rna seq
- electronic health record
- young adults
- lymph node metastasis
- high throughput
- artificial intelligence
- insulin resistance
- deep learning
- genome wide identification
- high throughput sequencing