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A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer

Nature Genetics volume 31, pages 141–149 (2002)Cite this article

Abstract

Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position.We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.

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Figure 1: Microarray analysis and categorization of genes by semi-quantitative RT–PCR.
Figure 2: Methylation analysis of group 1a and group 2 genes in a series of CRC cell lines.
Figure 3: RT–PCR analysis in various CRC cell lines.
Figure 4: MSP analysis of group 1a genes in primary CRC tissues (T) and normal colon mucosa (N) from the same affected individuals.
Figure 5: Summary of MSP analyses of six genes from group 1a in a series of human cancer cell lines of various origins.
Figure 6: Methylation and expression analysis of the SFRP genes.
Figure 7: Summary of MSP analyses of the SFRP genes in 124 primary CRC samples.

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Acknowledgements

We thank K. Bachman, K. Schuebel and H. Yoshikawa for providing cell lines; Y. Akiyama, M. Esteller and O. Galm for helpful comments on the manuscript; M. Toyota, M. Kusano, F. Itoh and K. Imai for providing CRC samples and M. House for providing normal colon samples.These studies were supported by grants from the National Cancer Institute.

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Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, 21231, Maryland, USA

    Hiromu Suzuki, Edward Gabrielson, Wei Chen, Ramaswamy Anbazhagan, Manon van Engeland, James G. Herman & Stephen B. Baylin

  2. Department of Pathology, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, 21231, Maryland, USA

    Edward Gabrielson & Ramaswamy Anbazhagan

  3. Predoctoral Training Program in Human Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Wei Chen & Stephen B. Baylin

  4. Department of Pathology, University Maastricht, The Netherlands

    Manon van Engeland

  5. Department of Epidemiology, University Maastricht, The Netherlands

    Matty P. Weijenberg

  6. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Stephen B. Baylin

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  1. Hiromu Suzuki
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Correspondence to Stephen B. Baylin.

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S.B.B. and J.G.H. are entitled to royalties from any sales of products licensed from their laboratories through the Johns Hopkins University Medical Institutions and marketed by Virco-Tibotech. These authors serve as consultants to Virco-Tibotech.

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Suzuki, H., Gabrielson, E., Chen, W. et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31, 141–149 (2002). https://doi.org/10.1038/ng892

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