Preferential activation of the hedgehog pathway by epigenetic modulations in HPV negative HNSCC identified with meta-pathway analysis.
Head and neck squamous cell carcinoma (HNSCC) is largely divided into two groups based on their etiology, human papillomavirus (HPV)-positive and -negative. Global DNA methylation changes are known to drive oncogene and tumor suppressor expression in primary HNSCC of both types. However, significant heterogeneity in DNA methylation within the groups results in different transcriptional profiles and clinical outcomes. We applied a meta-pathway analysis to link gene expression changes to DNA methylation in distinguishing HNSCC subtypes. This approach isolated specific epigenetic changes controlling expression in HPV- HNSCC that distinguish it from HPV+ HNSCC. Analysis of genes identified Hedgehog pathway activation specific to HPV- HNSCC. We confirmed that GLI1, the primary Hedgehog target, showed higher expression in tumors compared to normal samples with HPV- tumors having the highest GLI1 expression, suggesting that increased expression of GLI1 is a potential driver in HPV- HNSCC. Our algorithm for integration of DNA methylation and gene expression can infer biologically significant molecular pathways that may be exploited as therapeutics targets. Our results suggest that therapeutics targeting the Hedgehog pathway may be of benefit in HPV- HNSCC. Similar integrative analysis of high-throughput coupled DNA methylation and expression datasets may yield novel insights into deregulated pathways in other cancers.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
Elana J
EJ
Fertig
Ana
A
Markovic
Ludmila V
LV
Danilova
Daria A
DA
Gaykalova
Leslie
L
Cope
Christine H
CH
Chung
Michael F
MF
Ochs
Joseph A
JA
Califano
D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000821:virology; D016000:Cluster Analysis; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000821:virology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D027383:Papillomaviridae / Q000472:pathogenicity / Q000502:physiology; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
D004273:DNA, Neoplasm; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1