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Phenotype-Specific CpG Island Methylation Events in a Murine Model of Prostate Cancer

Departments of ¹ Cancer Genetics, ² Molecular Pharmacology and Cancer Therapeutics, and ³ Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Dominic J. Smiraglia, Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo Life Science Complex, Room L3-314, Buffalo Niagara Medical Campus, Elm + Carlton Streets, Buffalo, NY 14263. Phone: 716-845-1347; Fax: 716-845-1698; E-mail: Dominic.Smiraglia{at}roswellpark.org.

Key Words: CpG island • DNA methylation • TRAMP model

Aberrant DNA methylation plays a significant role in nearly all human cancers and may contribute to disease progression to advanced phenotypes. Study of advanced prostate cancer phenotypes in the human disease is hampered by limited availability of tissues. We therefore took advantage of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model to study whether three different phenotypes of TRAMP tumors (PRIM, late-stage primary tumors; AIP, androgen-independent primary tumors; and MET, metastases) displayed specific patterns of CpG island hypermethylation using Restriction Landmark Genomic Scanning. Each tumor phenotype displayed numerous hypermethylation events, with the most homogeneous methylation pattern in AIP and the most heterogeneous pattern in MET. Several loci displayed a phenotype-specific methylation pattern; the most striking pattern being loci methylated at high frequency in PRIM and AIP but rarely in MET. Examination of the mRNA expression of three genes, BC058385, Goosecoid, and Neurexin 2, which exhibited nonpromoter methylation, revealed increased expression associated with downstream methylation. Only methylated samples showed mRNA expression, in which tumor phenotype was a key factor determining the level of expression. The CpG island in the human orthologue of BC058385 was methylated in human AIP but not in primary androgen-stimulated prostate cancer or benign prostate. The clinical data show a proof-of-principle that the TRAMP model can be used to identify targets of aberrant CpG island methylation relevant to human disease. In conclusion, phenotype-specific hypermethylation events were associated with the overexpression of different genes and may provide new markers of prostate tumorigenesis. [Cancer Res 2008;68(11):4173–82]

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