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Methylation of Adenomatous Polyposis Coli in Endometrial Cancer Occurs More Frequently in Tumors with Microsatellite Instability Phenotype¹

Samuel Lunenfeld Research Institute [M. Z., A. S., A. M., J. K., B. B.], Department of Pathology and Laboratory Medicine [M. Z., A. S., A. M., B. B.], Mount Sinai Hospital, Toronto, Ontario, M5G 1X5; University Health Network, Toronto, Ontario, M5G 2C4 [W. C.]; and Department of Public Health Sciences [J. K.], and Department of Laboratory Medicine and Pathobiology, Faculty of Medicine [M. Z., A. M., W. C., B. B.], University of Toronto, Toronto, Ontario, M5S 1A1 Canada

Differential methylation is an important epigenetic control mechanism, which has been implicated in the development of a variety of cancers. Methylation of promoter regions of normally unmethylated tumor suppressor genes leads to transcriptional inactivation and ultimately to tumor formation. We hypothesized that epigenetic inactivation of adenomatous polyposis coli (APC), a key player in the suppressor pathway, may contribute to the development of endometrial cancer. We investigated APC methylation in endometrial adenocarcinoma specimens obtained from a series of patients (n = 114) and compared methylation profiles with microsatellite instability (MSI+) status. DNA microdissected from formalin-fixed, paraffin-embedded matched normal and tumor specimens, and a subset of associated endometrial hyperplasia was subjected to methylation-specific PCR of the APC promoter 1A region. Tumor-specific hypermethylation of APC with corresponding unmethylated normal endometrial tissue occurred in 43% (17 of 40) of MSI+ cases (P = 0.0007) and 16% (12 of 74) of microsatellite stable cases (P = 0.04). Interestingly, tumor tissue was unmethylated with normal tissue displaying APC methylation in 4% (5 of 114, 2MSI+ and 3 microsatellite stable) of cases. Endometrial cell lines AN3CA, RL95–2, and HEC-1B all displayed exclusive methylation of promoter 1A, and treatment of the AN3CA cell line with the demethylating agent 5-aza-2'-deoxycytidine exhibited re-expression of APC as confirmed by RT-PCR analysis. Our results demonstrate APC methylation in endometrial cancer for the first time and show that APC hypermethylation occurs at an increased frequency in MSI+ endometrial tumors (P = 0.01).

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