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Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype

The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In...

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Autores principales: Kawakami, K, Ooyama, A, Ruszkiewicz, A, Jin, M, Watanabe, G, Moore, J, Oka, T, Iacopetta, B, Minamoto, T
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391094/
https://www.ncbi.nlm.nih.gov/pubmed/18414409
http://dx.doi.org/10.1038/sj.bjc.6604346
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author Kawakami, K
Ooyama, A
Ruszkiewicz, A
Jin, M
Watanabe, G
Moore, J
Oka, T
Iacopetta, B
Minamoto, T
author_facet Kawakami, K
Ooyama, A
Ruszkiewicz, A
Jin, M
Watanabe, G
Moore, J
Oka, T
Iacopetta, B
Minamoto, T
author_sort Kawakami, K
collection PubMed
description The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of γ-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin.
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spelling pubmed-23910942009-09-10 Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype Kawakami, K Ooyama, A Ruszkiewicz, A Jin, M Watanabe, G Moore, J Oka, T Iacopetta, B Minamoto, T Br J Cancer Molecular Diagnostics The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of γ-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin. Nature Publishing Group 2008-05-06 2008-04-15 /pmc/articles/PMC2391094/ /pubmed/18414409 http://dx.doi.org/10.1038/sj.bjc.6604346 Text en Copyright © 2008 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Molecular Diagnostics
Kawakami, K
Ooyama, A
Ruszkiewicz, A
Jin, M
Watanabe, G
Moore, J
Oka, T
Iacopetta, B
Minamoto, T
Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title_full Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title_fullStr Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title_full_unstemmed Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title_short Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
title_sort low expression of γ-glutamyl hydrolase mrna in primary colorectal cancer with the cpg island methylator phenotype
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2391094/
https://www.ncbi.nlm.nih.gov/pubmed/18414409
http://dx.doi.org/10.1038/sj.bjc.6604346
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