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Decreased Fidelity in Replicating CpG Methylation Patterns in Cancer Cells

¹ Carcinogenesis Division and ² Cancer Genomics Division, National Cancer Center Research Institute, Tokyo, Japan

Requests for reprints: Toshikazu Ushijima, Carcinogenesis Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3547-5240; Fax: 81-3-5565-1753; E-mail: tushijim{at}ncc.go.jp.

The unmethylated or methylated status of individual CpG sites is faithfully copied into daughter cells. Here, we analyzed the fidelity in replicating their methylation statuses in cancer cells. A single cell was clonally expanded, and methylation statuses of individual CpG sites were determined for an average of 12.5 DNA molecules obtained from the expanded population. By counting the deviation from the original methylation patterns inferred, the number of errors was measured. The analysis was done in four gastric cancer cell lines for five CpG islands (CGI), and repeated six times (total 1,495 clones sequenced). HSC39 and HSC57 showed error rates <1.0 x 10^–3 errors per site per generation (99.90-100% fidelity) for all the five CGIs. In contrast, AGS showed significantly elevated error rates, mainly due to increased de novo methylation, in three CGIs (1.6- to 3.2-fold), and KATOIII showed a significantly elevated error rate in one CGI (2.2-fold). By selective amplification of fully methylated DNA molecules by methylation-specific PCR, those were stochastically detected in KATOIII and AGS but never in HSC39 and HSC57. When methylation of entire CGIs was examined for eight additional CGIs, KATOIII and AGS had frequent methylation, whereas HSC39 and HSC57 had few. KATOIII and AGS had four and eight times, respectively, as high expression levels of DNMT3B as HSC39. These data showed that some cancer cells have decreased fidelity in replicating methylation patterns in some CGIs, and that the decrease could lead to methylation of the entire CGIs.

Key Words: methylation pattern • maintenance methylation • de novo methylation • fidelity • CpG island • 02-12-03 DNA methylation/epigenetics • 02-12-03 DNA methylation/epigenetics • 02-12-03 DNA methylation/epigenetics • 02-10-03 Genetic instability: multistep progression • 02-12-00 Gene Expression, Chromatin Regulation, and Oncogenomics

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