© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 19, 1465-1472,
October 3, 2001
© 2001 Oxford University Press
Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells
Affiliations of authors: C. Nguyen, G. Liang, T. T. Nguyen, P. A. Jones (Department of Biochemistry and Molecular Biology), D. T.-W. Wei, S. Groshen (Department of Preventive Medicine), University of Southern California (USC)/Norris Comprehensive Cancer Center, Keck School of Medicine of the USC, Los Angeles; M. Lübbert, Department of Medicine, Division of Hematology/Oncology, University of Freiburg Medical Center, Germany; J.-H. Zhou, W. F. Benedict, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.
Correspondence to: Peter A. Jones, Ph.D., D.Sc., Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake Ave., Rm. 8302L, Los Angeles, CA (e-mail: jones_p{at}ccnt.hsc.usc.edu).
Background: Many cancers display alterations in methylation patterns of CpG islands—stretches of DNA rich in CpG dinucleotides often associated with gene promoters that are involved in initiation of gene transcription. This methylation may perturb expression of genes critical to the regulation of cell proliferation. Aberrant methylation is not limited to a few genes or to promoter regions but has been found on a genome-wide scale in a variety of neoplasias, including colorectal cancer and acute myelogenous leukemia. Our goal was to characterize, in a quantitative manner, the profiles of abnormally methylated genes that may be specific for different cancers. Methods: Using a quantitative assay, methylation-sensitive single nucleotide primer extension (MS-SNuPE), we have analyzed the methylation levels of promoter and exonic (coding region) CpG islands of two cyclin-dependent kinase inhibitors [p15(INK4B) and p16(INK4A)] and the PAX6 gene, which encodes a transcriptional factor involved in neuronal proliferation, in DNA samples taken from patients with chronic myelogenous leukemia, acute myelogenous leukemia, myelodysplastic syndrome, and colorectal cancer. Results: De novo methylation of all three exonic loci in tumors—relative to baseline levels found in nontumor tissue or blood—was observed in hematologic neoplasias and in solid tumors as well as in normal colonic tissue. However, methylation of promoter regions was more limited. Moreover, two different patterns of promoter methylation distinguished the leukemias from colorectal cancer: p15 promoter hypermethylation was found only in the leukemias, and p16 promoter hypermethylation occurred only in colon tumors. However, we did not address this issue prospectively; therefore, such an observation is only hypothesis generating. Conclusions: The methylation patterns that we observed suggest that exonic CpG islands are more susceptible to de novo methylation than promoter islands and that methylation may be seeded in exonic regions, from which it can spread to other islands, including promoter regions. Subsequent selection of cells with a growth advantage conferred by spread of methylation into and inactivation of a particular promoter might then contribute to the genesis of a specific type of cancer.
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