Identification and functional relevance of de novo DNA methylation in cancerous B-cell populations.
Epigenetic remodeling is a hallmark of cancer, with the frequent acquisition of de novo DNA methylation in CpG islands. However, the functional relevance of de novo DNA methylation in cancer is less well defined. To begin to address this issue in B-cells, we used BeadArray assays to survey the methylation status of over 1,500 cancer-related CpG loci in two molecular subtypes of diffuse large B-cell lymphoma (ABC-DLBCL and GCB-DLBCL) and cognate normal B-cell populations. We identified 81 loci that showed frequent de novo DNA methylation in GCB-DLBCL and 67 loci that showed frequent de novo DNA methylation in ABC-DLBCL. These de novo methylated CpG loci included reported targets of polycomb repressive complexes (PRC) in stem cells. All candidate loci in GCB-DLBCL are proximal to genes that are poorly expressed or silent in purified normal germinal center (GC) B-cells. This is consistent with the hypothesis that de novo DNA methylation in cancer is more frequently involved in the maintenance rather than the initiation of gene silencing (de novo repression). This suggests that epigenetic switching occurs during tumorigenesis with de novo DNA methylation locking in gene silencing normally mediated by transcriptional repressors. Furthermore, we propose that similar to de novo genetic mutations, the majority of de novo DNA methylation events observed in tumors are passengers not causally involved in tumorigenesis.
Wang
Xiao-Ming
XM
Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089, USA.
Greiner
Timothy C
TC
Bibikova
Marina
M
Pike
Brian L
BL
Siegmund
Kimberly D
KD
Sinha
Uttam K
UK
Müschen
Markus
M
Jaeger
Erich B
EB
Weisenburger
Dennis D
DD
Chan
Wing C
WC
Shibata
Darryl
D
Fan
Jian-Bing
JB
Hacia
Joseph G
JG
D001402:B-Lymphocytes / Q000473:pathology*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics
D063146:Polycomb-Group Proteins; D012097:Repressor Proteins