Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau SK et al.. Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci USA 104: 5527-5532

Division of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2007; 104(13):5527-32. DOI: 10.1073/pnas.0701059104
Source: PubMed


De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancer-associated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7- and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.

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Available from: Gerd Pfeifer, Dec 19, 2014
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    • "Dysregulated behavior of HOX genes has been observed in ovarian cancer [38]. Early stage HOXA9 methylation has been identified in lung cancer and used in early detection and prognosis [39,40]. Our analysis found HOX genes in all stages, with hypermethylation in Stages I and III, hypomethylation in Stage II. "
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    BMC Systems Biology 12/2013; 7(1):141. DOI:10.1186/1752-0509-7-141 · 2.44 Impact Factor
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    • "As DNA methylation is a key component of genome regulation in normal and cancer tissues, we evaluated the methylation status of three GSC lines. The array platform used in this study covers 27800 CGIs of the human genome [42] and all the data (percentages and frequencies) are referred to the total number of CGIs included in the array. Raw data were processed as described in the material and methods section and they were deposited in the NCBI's Gene Expression Omnibus [40] and are accessible through GEO Series accession number GSE41824. "
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    PLoS ONE 02/2013; 8(2):e57462. DOI:10.1371/journal.pone.0057462 · 3.23 Impact Factor
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    • "En1 hypermethylation (human cell lines & tumours) Lung Methylated-CpG island recovery [74] Colorectal Methylation-specific PCR [75] [76] Astrocytoma Methylated-CpG island recovery [77] Prostate Methylated-CpG island amplification and microarray [78] Salivary gland (Adenoid cystic) Methylated CpG island amplification and microarray [81] En2 hypermethylation (human cell lines & tumours) Lung Methylated-CpG island recovery [74] Follicular lymphoma Methylation-specific PCR [79] "
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    ABSTRACT: Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.
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