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

Rafael Guerrero-Preston, Christina Michailidi, Luigi Marchionni, Curtis R. Pickering, Mitchell J. Frederick, Jeffrey N. Myers, Srinivasan Yegnasubramanian, Tal Hadar, Maartje G. Noordhuis, Veronika Zizkova, Elana Fertig, Nishant Agrawal, William Westra, Wayne Koch, Joseph Califano, Victor E. Velculescu, David Sidransky*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    86 Citations (Scopus)
    293 Downloads (Pure)

    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 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.

    Original languageEnglish
    Pages (from-to)1031-1046
    Number of pages16
    JournalEpigenetics
    Volume9
    Issue number7
    DOIs
    Publication statusPublished - Jul-2014

    Keywords

    • Head and Neck Squamous Cell Carcinoma
    • Tumor Suppressor Genes
    • DNA methylation
    • somatic mutations
    • integration analysis
    • SQUAMOUS-CELL CARCINOMA
    • DNA METHYLATION
    • PROSTATE-CANCER
    • SET ENRICHMENT
    • EXPRESSION
    • GENOME
    • HYPERMETHYLATION
    • DIFFERENTIATION
    • CHEMOPREVENTION
    • ACTIVATION

    Cite this