Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.
Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.
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DOI：
10.4161/epi.29025
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发表时间：
2014-07
期刊：
影响因子：
3.7
通讯作者：
Sidransky D
中科院分区：
文献类型：
--
作者：
Guerrero-Preston R;Michailidi C;Marchionni L;Pickering CR;Frederick MJ;Myers JN;Yegnasubramanian S;Hadar T;Noordhuis MG;Zizkova V;Fertig E;Agrawal N;Westra W;Koch W;Califano J;Velculescu VE;Sidransky D
肿瘤抑制基因（TSGs）通常通过体细胞突变和/或启动子甲基化失活;然而，最近的高通量基因组研究尚未确定这两种机制失活的关键TSGs。我们在原发性头颈部鳞状细胞癌（HNSCC）肿瘤和匹配的悬雍垂腭咽成形术组织样本（UPPP）中进行了基于甲基化结合结构域测序（MBD-seq）、450 K甲基化阵列、全外显子组测序和全基因组基因表达阵列的综合分子分析。我们发现了186个具有癌症特异性启动子甲基化的下调基因，包括PAX 1和PAX 5，并确定了10个关键肿瘤抑制基因（GABRB 3、HOXC 12、PARP 15、SLCO 4C 1、CDKN 2A、PAX 1、PIK 3AP 1、HOXC 6、PLCB 1和ZIC 4），这些基因因启动子甲基化和/或体细胞突变而失活。在发现的具有双重失活机制的新型肿瘤抑制基因中，我们发现PAX基因家族转录因子的基因组和表观基因组改变的频率很高，这些基因组和表观基因组改变选择性地影响经典的NOTCH和TP 53途径，以确定细胞命运、细胞存活和基因组维持。我们的研究结果强调了在基因组和表观基因组水平评估TSGs以确定HNSCC中的关键途径的重要性，同时启动子甲基化和体细胞突变解除了调控。
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.