Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.
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.
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.
Rafael
R
Guerrero-Preston
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
Christina
C
Michailidi
Department of Oncology Biostatistics; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
Luigi
L
Marchionni
Department of Head and Neck Surgery; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
Curtis R
CR
Pickering
Department of Head and Neck Surgery; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
Mitchell J
MJ
Frederick
Department of Head and Neck Surgery; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
Jeffrey N
JN
Myers
Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
Srinivasan
S
Yegnasubramanian
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
Tal
T
Hadar
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.
Maartje G
MG
Noordhuis
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.
Veronika
V
Zizkova
Division of Biostatistics and Bioinformatics; Department of Oncology; Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
Elana
E
Fertig
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.
Nishant
N
Agrawal
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
William
W
Westra
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
Wayne
W
Koch
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.
Joseph
J
Califano
Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University; Baltimore, MD USA.
Victor E
VE
Velculescu
Department of Otolaryngology and Head and Neck Surgery; Johns Hopkins University; School of Medicine; Baltimore, MD USA.
David
D
Sidransky
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C497761:NOTCH1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D051761:Paired Box Transcription Factors; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; C070835:PAX1 transcription factor
DNA methylation; Head and Neck Squamous Cell Carcinoma; Tumor Suppressor Genes; integration analysis; somatic mutations