TY - JOUR
T1 - Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer
AU - Guerrero-Preston, Rafael
AU - Michailidi, Christina
AU - Marchionni, Luigi
AU - Pickering, Curtis R.
AU - Frederick, Mitchell J.
AU - Myers, Jeffrey N.
AU - Yegnasubramanian, Srinivasan
AU - Hadar, Tal
AU - Noordhuis, Maartje G.
AU - Zizkova, Veronika
AU - Fertig, Elana
AU - Agrawal, Nishant
AU - Westra, William
AU - Koch, Wayne
AU - Califano, Joseph
AU - Velculescu, Victor E.
AU - Sidransky, David
N1 - Funding Information:
National Cancer Institute grants U01CA84986 and K01CA164092 and CA121113; National Institute of Dental and Craniofacial Research grants P50DE019032 Head and Neck Cancer SPORE, and RC2 DE20957, and the Commonwealth Fund supported this research. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2014/1/5
Y1 - 2014/1/5
N2 - 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 down-regulated 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.
AB - 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 down-regulated 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.
KW - DNA methylation
KW - Head and neck squamous cell carcinoma
KW - Integration analysis
KW - Somatic mutations
KW - Tumor suppressor genes
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U2 - 10.4161/epi.29025
DO - 10.4161/epi.29025
M3 - Article
C2 - 24786473
AN - SCOPUS:84902599616
SN - 1559-2294
VL - 9
SP - 1031
EP - 1046
JO - Epigenetics
JF - Epigenetics
IS - 7
ER -