CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells.
Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology.
Opavsky
Rene
R
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
Wang
Shu-Huei
SH
Trikha
Prashant
P
Raval
Aparna
A
Huang
Yuan
Y
Wu
Yue-Zhong
YZ
Rodriguez
Benjamin
B
Keller
Benjamin
B
Liyanarachchi
Sandya
S
Wei
Guo
G
Davuluri
Ramana V
RV
Weinstein
Michael
M
Felsher
Dean
D
Ostrowski
Michael
M
Leone
Gustavo
G
Plass
Christoph
C
D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D019076:Transgenes
D004273:DNA, Neoplasm; D016271:Proto-Oncogene Proteins c-myc