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GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer

Debby MEI Hellebrekers, Marjolein HFM Lentjes, Sandra M van den Bosch, Veerle Melotte, Kim AD Wouters, Kathleen LJ Daenen, Kim M Smits, Yohimitsu Akiyama, Yasuhito Yuasa and Silvia Sanduleanu, et al. (2009) CLINICAL CANCER RESEARCH. 15(12). p.3990-3997
abstract
Purpose: The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer. Experimental Design: Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines. Results: GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% Cl), 55-88%] and specificity of 84% (95% Cl, 74-95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% Cl, 37-65%) and specificity of 93% (95% Cl, 84-100%) in the validation set. Conclusions: Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
LUNG-CANCER, HYPERMETHYLATION, PROMOTER METHYLATION, FECAL-OCCULT-BLOOD, TRANSCRIPTION FACTORS, ULCERATIVE-COLITIS, NETHERLANDS COHORT, CONTROLLED TRIAL, COLON-CANCER, MULTIPLE GENES
journal title
CLINICAL CANCER RESEARCH
Clin. Cancer Res.
volume
15
issue
12
pages
8 pages
Web of Science type
Article
Web of Science id
000267080800013
JCR category
ONCOLOGY
JCR impact factor
6.747 (2009)
JCR rank
16/163 (2009)
JCR quartile
1 (2009)
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-09-0055
language
English
UGent publication?
no
classification
A1
id
791368
handle
http://hdl.handle.net/1854/LU-791368
date created
2009-11-28 22:46:35
date last changed
2010-01-04 11:53:40
@article{791368,
  abstract     = {Purpose: The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer.
Experimental Design: Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines.
Results: GATA4/5 methylation was observed in 70\% (63/90) and 79\% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6\% (5 of 88, GATA4; P {\textlangle} 0.001) and 13\% (13 of 100, GATA5; P {\textlangle} 0.001). GATA4/5 overexpression suppressed colony formation (P {\textlangle} 0.005), proliferation (P {\textlangle} 0.001), migration (P {\textlangle} 0.05), invasion (P {\textlangle} 0.05), and anchorage-independent growth (P {\textlangle} 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71\% [95\% confidence interval (95\% Cl), 55-88\%] and specificity of 84\% (95\% Cl, 74-95\%) for colorectal cancer detection in the training set, and a sensitivity of 51\% (95\% Cl, 37-65\%) and specificity of 93\% (95\% Cl, 84-100\%) in the validation set.
Conclusions: Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.},
  author       = {Hellebrekers, Debby MEI and Lentjes, Marjolein HFM and van den Bosch, Sandra M and Melotte, Veerle and Wouters, Kim AD and Daenen, Kathleen LJ and Smits, Kim M and Akiyama, Yohimitsu and Yuasa, Yasuhito and Sanduleanu, Silvia and Khalid-de Bakker, Carolina AJ and Jonkers, Daisy and Weijenberg, Matty P and Louwagie, Joost and Van Criekinge, Wim and Carvalho, Beatriz and Meijer, Gerrit A and Baylin, Stephen B and Herman, James G and de Bruine, Adriaan P and van Engeland, Manon},
  issn         = {1078-0432},
  journal      = {CLINICAL CANCER RESEARCH},
  keyword      = {LUNG-CANCER,HYPERMETHYLATION,PROMOTER METHYLATION,FECAL-OCCULT-BLOOD,TRANSCRIPTION FACTORS,ULCERATIVE-COLITIS,NETHERLANDS COHORT,CONTROLLED TRIAL,COLON-CANCER,MULTIPLE GENES},
  language     = {eng},
  number       = {12},
  pages        = {3990--3997},
  title        = {GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-09-0055},
  volume       = {15},
  year         = {2009},
}

Chicago
Hellebrekers, Debby MEI, Marjolein HFM Lentjes, Sandra M van den Bosch, Veerle Melotte, Kim AD Wouters, Kathleen LJ Daenen, Kim M Smits, et al. 2009. “GATA4 and GATA5 Are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer.” Clinical Cancer Research 15 (12): 3990–3997.
APA
Hellebrekers, D. M., Lentjes, M. H., van den Bosch, S. M., Melotte, V., Wouters, K. A., Daenen, K. L., Smits, K. M., et al. (2009). GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. CLINICAL CANCER RESEARCH, 15(12), 3990–3997.
Vancouver
1.
Hellebrekers DM, Lentjes MH, van den Bosch SM, Melotte V, Wouters KA, Daenen KL, et al. GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. CLINICAL CANCER RESEARCH. 2009;15(12):3990–7.
MLA
Hellebrekers, Debby MEI, Marjolein HFM Lentjes, Sandra M van den Bosch, et al. “GATA4 and GATA5 Are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer.” CLINICAL CANCER RESEARCH 15.12 (2009): 3990–3997. Print.