Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide methylation in paired lung tumor/non-tumor samples using the HELP assay

ABSTRACT: In lung cancer, hypermethylation of specific gene promoters has been found during the progressive carcinogenesis. The identification of common methylation events will aid in the understanding of molecular events during neoplastic transformation and help develop biomarkers for cancer with high predictive and diagnostic value. To explore common methylation events on a genome-wide scale in lung cancer, we analyzed the methylation profiles of paired NSCLC tumor and far adjacent non-tumor samples using the HELP-microarray assay, which yields information on 1.2 million fragments throughout the genome. In this study, 24 pairs of tumor and adjacent non-tumor samples were analyzed using the HELP assay. At p = 5E-6, we identified 26,138 differentially methylated fragments (corresponding to 2 CpG sites each) in tumor versus non-tumor. The overall trend was consistent with genome-wide hypomethylation and locus specific hypermethylation (localized to CG-island containing promoters). We could identify both known and novel regions of the genome as well as specific gene-promoters that are hypermethylated in tumor versus non-tumor. The HELPassay: HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction [PCR] assay 24 pairs of NSCLC subjects, tumor and paired non-tumor samples from each subject were analyzed. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample. Samples were compared intra-subject between tumor and adjacent non-tumor for these differential methylation profiles and the overall significant changes across 24 subjects were identified.

ORGANISM(S): Homo sapiens

SUBMITTER: Miao Shi

PROVIDER: E-GEOD-35520 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis compared to essential thrombocytosis (ET) or polycythemia vera (PV), the molecular distinctions between these subgroups are not well elucidated. We performed the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in PV, ET and PMF samples compared with healthy controls. We determined that PV and ET are characterized by aberrant promoter hypermethylation while PMF is an epigenetically distinct subgroup characterized by both aberrant hyper and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non CpG island loci, demonstrating further qualitative differences between the disease subgroups. The differentially methylated genes in PV and ET were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1 (NFI), LEF1 and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of MPNs with TET2 mutations demonstrated decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was demonstrated by sensitivity of MPN derived cell lines to decitabine. These results demonstrate epigenetic differences between PMF and PV/ET and reveal methylomic signatures of ASXL1 and TET2 mutations. The study population consisted of 26 MPN patients (6 cases of ET, 8 cases of PV and 12 cases of PMF) and 3 healthy controls. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample. The purpose of this study was to assess genome wide patterns of DNA methylation across the MPN stratified by disease class.

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Genome-wide methylation in paired lung tumor/non-tumor samples using the HELP assay

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