The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.

Development of colorectal cancer (CRC) can occur both via gene mutations in tumor suppressor genes and oncogenes, as well as via epigenetic changes, including DNA methylation. Site-specific methylation in CRC regulates expression of tumor-associated genes. Right-sided colon tumors more frequently ha...

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Autores principales:	Ashwin A Dihal, Arnoud Boot, Eddy H van Roon, Melanie Schrumpf, Arantza Fariña-Sarasqueta, Marta Fiocco, Eliane C M Zeestraten, Peter J K Kuppen, Hans Morreau, Tom van Wezel, Judith M Boer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d675d3f538cd4653b1f1899bf7926719
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spelling	oai:doaj.org-article:d675d3f538cd4653b1f1899bf79267192021-11-18T08:47:52ZThe homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.1932-620310.1371/journal.pone.0079898https://doaj.org/article/d675d3f538cd4653b1f1899bf79267192013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24244575/?tool=EBIhttps://doaj.org/toc/1932-6203Development of colorectal cancer (CRC) can occur both via gene mutations in tumor suppressor genes and oncogenes, as well as via epigenetic changes, including DNA methylation. Site-specific methylation in CRC regulates expression of tumor-associated genes. Right-sided colon tumors more frequently have BRAF (p.V600E) mutations and have higher methylation grades when compared to left-sided malignancies. The aim of this study was to identify DNA methylation changes associated with BRAF (p.V600E) mutation status. We performed methylation profiling of colon tumor DNA, isolated from frozen sections enriched for epithelial cells by macro-dissection, and from paired healthy tissue. Single gene analyses comparing BRAF (p.V600E) with BRAF wild type revealed MEIS1 as the most significant differentially methylated gene (log2 fold change: 0.89, false discovery rate-adjusted P-value 2.8*10(-9)). This finding was validated by methylation-specific PCR that was concordant with the microarray data. Additionally, validation in an independent cohort (n=228) showed a significant association between BRAF (p.V600E) and MEIS1 methylation (OR: 13.0, 95% CI: 5.2 - 33.0, P<0.0001). MEIS1 methylation was associated with decreased MEIS1 gene expression in both patient samples and CRC cell lines. The same was true for gene expression of a truncated form of MEIS1, MEIS1 D27 , which misses exon 8 and has a proposed tumor suppression function. To trace the origin of MEIS1 promoter methylation, 14 colorectal tumors were flow-sorted. Four out of eight BRAF (p.V600E) tumor epithelial fractions (50%) showed MEIS1 promoter methylation, as well as three out of eight BRAF (p.V600E) stromal fractions (38%). Only one out of six BRAF wild type showed MEIS1 promoter methylation in both the epithelial tumor and stromal fractions (17%). In conclusion, BRAF (p.V600E) colon tumors showed significant MEIS1 promoter methylation, which was associated with decreased MEIS1 gene expression.Ashwin A DihalArnoud BootEddy H van RoonMelanie SchrumpfArantza Fariña-SarasquetaMarta FioccoEliane C M ZeestratenPeter J K KuppenHans MorreauTom van WezelJudith M BoerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e79898 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ashwin A Dihal Arnoud Boot Eddy H van Roon Melanie Schrumpf Arantza Fariña-Sarasqueta Marta Fiocco Eliane C M Zeestraten Peter J K Kuppen Hans Morreau Tom van Wezel Judith M Boer The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
description	Development of colorectal cancer (CRC) can occur both via gene mutations in tumor suppressor genes and oncogenes, as well as via epigenetic changes, including DNA methylation. Site-specific methylation in CRC regulates expression of tumor-associated genes. Right-sided colon tumors more frequently have BRAF (p.V600E) mutations and have higher methylation grades when compared to left-sided malignancies. The aim of this study was to identify DNA methylation changes associated with BRAF (p.V600E) mutation status. We performed methylation profiling of colon tumor DNA, isolated from frozen sections enriched for epithelial cells by macro-dissection, and from paired healthy tissue. Single gene analyses comparing BRAF (p.V600E) with BRAF wild type revealed MEIS1 as the most significant differentially methylated gene (log2 fold change: 0.89, false discovery rate-adjusted P-value 2.8*10(-9)). This finding was validated by methylation-specific PCR that was concordant with the microarray data. Additionally, validation in an independent cohort (n=228) showed a significant association between BRAF (p.V600E) and MEIS1 methylation (OR: 13.0, 95% CI: 5.2 - 33.0, P<0.0001). MEIS1 methylation was associated with decreased MEIS1 gene expression in both patient samples and CRC cell lines. The same was true for gene expression of a truncated form of MEIS1, MEIS1 D27 , which misses exon 8 and has a proposed tumor suppression function. To trace the origin of MEIS1 promoter methylation, 14 colorectal tumors were flow-sorted. Four out of eight BRAF (p.V600E) tumor epithelial fractions (50%) showed MEIS1 promoter methylation, as well as three out of eight BRAF (p.V600E) stromal fractions (38%). Only one out of six BRAF wild type showed MEIS1 promoter methylation in both the epithelial tumor and stromal fractions (17%). In conclusion, BRAF (p.V600E) colon tumors showed significant MEIS1 promoter methylation, which was associated with decreased MEIS1 gene expression.
format	article
author	Ashwin A Dihal Arnoud Boot Eddy H van Roon Melanie Schrumpf Arantza Fariña-Sarasqueta Marta Fiocco Eliane C M Zeestraten Peter J K Kuppen Hans Morreau Tom van Wezel Judith M Boer
author_facet	Ashwin A Dihal Arnoud Boot Eddy H van Roon Melanie Schrumpf Arantza Fariña-Sarasqueta Marta Fiocco Eliane C M Zeestraten Peter J K Kuppen Hans Morreau Tom van Wezel Judith M Boer
author_sort	Ashwin A Dihal
title	The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
title_short	The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
title_full	The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
title_fullStr	The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
title_full_unstemmed	The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.
title_sort	homeobox gene meis1 is methylated in braf (p.v600e) mutated colon tumors.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d675d3f538cd4653b1f1899bf7926719
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The homeobox gene MEIS1 is methylated in BRAF (p.V600E) mutated colon tumors.

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