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Epigenetics. 2014 Jul;9(7):1031-46. doi: 10.4161/epi.29025. Epub 2014 May 1.

Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.

Author information

1
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA; Department of Obstetrics and Gynecology; University of Puerto Rico School of Medicine; Río Piedras, Puerto Rico.
2
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
3
Department of Oncology Biostatistics; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
4
Department of Head and Neck Surgery; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
5
Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
6
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA; Department of Otorhinolaryngology-Head and Neck Surgery; University of Groningen; University Medical Center; Groningen, The Netherlands.
7
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA; Laboratory of Molecular Pathology and Institute of Molecular and Translational Medicine; Faculty of Medicine and Dentistry; Palacky University; Olomouc, Czech Republic.
8
Division of Biostatistics and Bioinformatics; Department of Oncology; Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
9
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
10
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA; Milton J. Dance Head and Neck Center; Greater Baltimore Medical Center; Baltimore, MD USA.

Abstract

Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.

KEYWORDS:

DNA methylation; Head and Neck Squamous Cell Carcinoma; Tumor Suppressor Genes; integration analysis; somatic mutations

PMID:
24786473
PMCID:
PMC4143405
DOI:
10.4161/epi.29025
[Indexed for MEDLINE]
Free PMC Article

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