TY - JOUR
T1 - Alterations in DNA methylation
T2 - A fundamental aspect of neoplasia
AU - Baylin, Stephen B.
AU - Herman, James G.
AU - Graff, Jeremy R.
AU - Vertino, Paula M.
AU - Issa, Jean Pierre
N1 - Funding Information:
We gratefully acknowledge all of the colleagues over the years who have contributed to studies in our own laboratories and the many workers in the DNA methylatioii field whose work is cited in this review. Of course, space limitations preclude referencing many other papers that have provided important data, and we apologize for those exclusions. We thank Tammy M. Means for invaluable secretarial services. Portions of work performed in the authors’ laboratories were supported by National Cancer Institute grants #CA43318, #CA.54396, and #SPOCA58184 and by a grant from the Tobacco Research Council (#1987B). J.G.H. is recipient of a Valvano Fouindation Research Award and J.P.I. of a Kiminel Foundation Award.
PY - 1997
Y1 - 1997
N2 - Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA- methyltransferase (DNA-MTase) activity. Each component of this 'methylation imbalance' may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may wall be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
AB - Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA- methyltransferase (DNA-MTase) activity. Each component of this 'methylation imbalance' may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may wall be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.
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M3 - Review article
C2 - 9338076
AN - SCOPUS:0030846212
SN - 0065-230X
VL - 72
SP - 141
EP - 196
JO - Advances in cancer research
JF - Advances in cancer research
ER -