Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential.

• MeSH
• dospělí MeSH
• epigenomika * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové buněčné linie MeSH
• nádory hlavy a krku genetika   patologie   MeSH
• pohyb buněk genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory Notch genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• RNA interference MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• shluková analýza MeSH
• signální transdukce genetika   MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• tumor supresorové geny * MeSH
• ubikvitinligasy genetika   MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC.

• MeSH
• infekce papilomavirem genetika   metabolismus   MeSH
• lidé MeSH
• metylace DNA MeSH
• nádorové buněčné linie MeSH
• nádory hlavy a krku genetika   metabolismus   virologie   MeSH
• NF-kappa B genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• signální transdukce MeSH
• spinocelulární karcinom genetika   metabolismus   virologie   MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH