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Epigenetic alterations in neoplasia
Seminars in Cancer Biology 19 (2009) 135
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Epigenetic alterations in neoplasia
In multicellular organisms coregulated expression of gene-sets could either be achieved through repetitive sequences located in the regulatory regions of coexpressed (or cosilenced) promoters or by organizing gene-batteries into higher-order chromosomal structures within interphase nuclei. The establishment of cell identity and cell-type-specific gene expression patterns involves silencing of the majority of genes via epigenetic regulatory mechanisms. Dysregulation of gene expression due to genetic changes or epigenetic alterations may result in malignant transformation that is either a multistep process, or may happen in a single step as demonstrated in case of certain oncovirus-induced neoplasms. Although this issue focuses on the role of epigenetic dysregulation and epigenetic reprogramming in carcinogenesis and tumor progression, genetic changes (and their epigenetic consequences) are also discussed wherever appropriate. Walter Doerfler describes a unique model system of human adenovirus type 12 induced neoplasms (undifferentiated neuroectodermal tumors) in Syrian hamsters. The viral genome integrates into the host cell DNA resulting in changes of cellular DNA methylation both at the insertion site and at remote cellular loci. In parallel, the integrated adenoviral genome also undergoes de novo CpG methylation, with the exception of certain unmethylated isles. The consequences of foreign DNA insertion into other mammalian organisms are also discussed. Anita Szalmás and József Kónya review the epigenetic consequences of human papillomavirus infection of the ectocervix/transformation zone, and endocervix, respectively. Similarly to the adenovirus model, integration of the viral genome is an important step in cervical carcinogenesis as well, but the sets of cellular promoters hypermethylated in this process varies depending on the histology of the developing tumors (squamous cell carcinomas; adenocarcinomas). Shara N. Pantry and Peter G. Medveczky discuss how epigenetic regulators influence the episomal (non-integrated) genomes of Kaposi’s sarcoma-associated herpesvirus (KSHV). They focus on the modifications controlling episomal replication during latency and influencing the switch between latency and lytic (productive) replication, and summarize the role of the latency associated nuclear antigen (LANA) in altering methylation of the host cell DNA. Hans Helmut Niller, Hans Wolf and Janos Minarovits give a concise summary of epigenetic alterations occuring in Epstein-Barr virus (EBV)-associated lymphomas (Burkitt’s lymphoma, Hodgkin’s
1044-579X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2009.02.014
disease) and carcinomas (nasopharyngeal carcinoma, gastric carcinoma). Although the EBV oncoprotein LMP1 (latent membrane protein 1) can up-regulate DNA methyltrasnferases, it is absent in certain EBV-associated tumors, implicating other viral latency products in epigenetic dysregulation. Amy M. Dworkin, Tim H.-M. Huang and Amanda Ewart Toland overview the epigenetic alterations detected in hormone-dependent and hormone-independent breast carcinomas. They also discuss epigenetically-mediated gene silencing in the context of field cancerization and the microenvironment of tumor cells. Wolfgang A. Schulz and Michèle J. Hoffmann deal with epigenetic changes recorded during development and progression of prostate cancer. They also give a critical evaluation of current ideas regarding the etiology and pathogenesis of this initially hormone-dependent neoplasm. Gerd P. Pfeifer and Tibor A. Rauch describe the use of a genomescale mapping technique for CpG methylation in characterizing lung carcinomas. A large fraction of tumor-specifically methylated CpG islands is targeted by the Polycomb complex in embryonic stem cells, whereas hypomethylated DNA regions usually correspond to repetitive sequence classes. Raman P. Nagarajan and Joseph F. Costello overview the intricate interactions of epigenetic regulatory mechanisms (DNA methylation and demethylation, histone modifications, Polycomb complexes, microRNAs) contributing to the development and progression of glioblastoma multiforme (GBM). They also discuss the epigenetic therapy of GBM, that may be guided by patient-specific epigenetic profiling in the future. Shu-Huei Hsiao, Tim H.-M. Huang and Yu-Wei Leu outline the idea that signal-specific and lineage-specific changes of DNA methylation may provide a record for past cellular evolution. Thus, neoplastic cells in a tumor may share similar molecular marks (i.e. molecular memories reflecting cell fate changes) that may differ from those of their normal counterparts and could be used as epigenetic biomarkers, in the coming era of lineage- dependent epigenomics. Janos Minarovits Microbiological Research Group, National Center for Epidemiology, H-1529 Budapest, Pihenö u. 1, Hungary E-mail address: [email protected]
Contents lists available at ScienceDirect
Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer
Editorial
Epigenetic alterations in neoplasia
In multicellular organisms coregulated expression of gene-sets could either be achieved through repetitive sequences located in the regulatory regions of coexpressed (or cosilenced) promoters or by organizing gene-batteries into higher-order chromosomal structures within interphase nuclei. The establishment of cell identity and cell-type-specific gene expression patterns involves silencing of the majority of genes via epigenetic regulatory mechanisms. Dysregulation of gene expression due to genetic changes or epigenetic alterations may result in malignant transformation that is either a multistep process, or may happen in a single step as demonstrated in case of certain oncovirus-induced neoplasms. Although this issue focuses on the role of epigenetic dysregulation and epigenetic reprogramming in carcinogenesis and tumor progression, genetic changes (and their epigenetic consequences) are also discussed wherever appropriate. Walter Doerfler describes a unique model system of human adenovirus type 12 induced neoplasms (undifferentiated neuroectodermal tumors) in Syrian hamsters. The viral genome integrates into the host cell DNA resulting in changes of cellular DNA methylation both at the insertion site and at remote cellular loci. In parallel, the integrated adenoviral genome also undergoes de novo CpG methylation, with the exception of certain unmethylated isles. The consequences of foreign DNA insertion into other mammalian organisms are also discussed. Anita Szalmás and József Kónya review the epigenetic consequences of human papillomavirus infection of the ectocervix/transformation zone, and endocervix, respectively. Similarly to the adenovirus model, integration of the viral genome is an important step in cervical carcinogenesis as well, but the sets of cellular promoters hypermethylated in this process varies depending on the histology of the developing tumors (squamous cell carcinomas; adenocarcinomas). Shara N. Pantry and Peter G. Medveczky discuss how epigenetic regulators influence the episomal (non-integrated) genomes of Kaposi’s sarcoma-associated herpesvirus (KSHV). They focus on the modifications controlling episomal replication during latency and influencing the switch between latency and lytic (productive) replication, and summarize the role of the latency associated nuclear antigen (LANA) in altering methylation of the host cell DNA. Hans Helmut Niller, Hans Wolf and Janos Minarovits give a concise summary of epigenetic alterations occuring in Epstein-Barr virus (EBV)-associated lymphomas (Burkitt’s lymphoma, Hodgkin’s
1044-579X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2009.02.014
disease) and carcinomas (nasopharyngeal carcinoma, gastric carcinoma). Although the EBV oncoprotein LMP1 (latent membrane protein 1) can up-regulate DNA methyltrasnferases, it is absent in certain EBV-associated tumors, implicating other viral latency products in epigenetic dysregulation. Amy M. Dworkin, Tim H.-M. Huang and Amanda Ewart Toland overview the epigenetic alterations detected in hormone-dependent and hormone-independent breast carcinomas. They also discuss epigenetically-mediated gene silencing in the context of field cancerization and the microenvironment of tumor cells. Wolfgang A. Schulz and Michèle J. Hoffmann deal with epigenetic changes recorded during development and progression of prostate cancer. They also give a critical evaluation of current ideas regarding the etiology and pathogenesis of this initially hormone-dependent neoplasm. Gerd P. Pfeifer and Tibor A. Rauch describe the use of a genomescale mapping technique for CpG methylation in characterizing lung carcinomas. A large fraction of tumor-specifically methylated CpG islands is targeted by the Polycomb complex in embryonic stem cells, whereas hypomethylated DNA regions usually correspond to repetitive sequence classes. Raman P. Nagarajan and Joseph F. Costello overview the intricate interactions of epigenetic regulatory mechanisms (DNA methylation and demethylation, histone modifications, Polycomb complexes, microRNAs) contributing to the development and progression of glioblastoma multiforme (GBM). They also discuss the epigenetic therapy of GBM, that may be guided by patient-specific epigenetic profiling in the future. Shu-Huei Hsiao, Tim H.-M. Huang and Yu-Wei Leu outline the idea that signal-specific and lineage-specific changes of DNA methylation may provide a record for past cellular evolution. Thus, neoplastic cells in a tumor may share similar molecular marks (i.e. molecular memories reflecting cell fate changes) that may differ from those of their normal counterparts and could be used as epigenetic biomarkers, in the coming era of lineage- dependent epigenomics. Janos Minarovits Microbiological Research Group, National Center for Epidemiology, H-1529 Budapest, Pihenö u. 1, Hungary E-mail address: [email protected]