Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.

• MeSH
• chemorezistence * MeSH
• CpG ostrůvky MeSH
• dítě MeSH
• juvenilní myelomonocytární leukemie diagnóza   metabolismus   patologie   MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy, pár 7 MeSH
• metylace DNA * MeSH
• mladiství MeSH
• monozomie MeSH
• mutace MeSH
• předškolní dítě MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• protein - isoformy genetika   metabolismus   MeSH
• proteiny aktivující GTPasu ras genetika   metabolismus   MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   metabolismus   MeSH
• umlčování genů MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• MeSH
• aktivátorový protein specifický pro B-buňky genetika   metabolismus   MeSH
• CpG ostrůvky MeSH
• kohortové studie MeSH
• lidé MeSH
• metylace DNA * MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory hlavy a krku genetika   metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• receptor Notch1 genetika   metabolismus   MeSH
• spinocelulární karcinom genetika   metabolismus   MeSH
• transkripční faktory paired box genetika   metabolismus   MeSH
• tumor supresorové geny * MeSH
• umlčování genů * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH