Epigenetic Alterations (epigenetic + alteration)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Epigenetic changes in cancer,

APMIS, Issue 10 2007
KIRSTEN GRØNBÆK
A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. Basically, this process is directed by changes in two different classes of genes: Tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. Since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. Cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. Epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in carcinogenesis. These epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the DNA is wrapped, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself. Methylation of clusters of CpGs called "CpG-islands" in the promoters of genes has been associated with heritable gene silencing. The present review will focus on how disruption of the epigenome can contribute to cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. Treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. Accordingly, in the clinical setting, DNA methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic therapy has recently been approved by the United States Food and Drug Administration (US FDA) for use in the treatment of myelodysplastic syndrome (MDS) and primary cutaneous T-cell lymphoma (CTCL). [source]


Fetal programming and fetal psychology

INFANT AND CHILD DEVELOPMENT, Issue 1 2010
Peter T. Ellison
Abstract The introduction of the ,fetal programming hypothesis', first in epidemiology, subsequently in a broad range of disciplines concerned with developmental biology, has generated new interest in phenotypic plasticity, the mechanisms that govern it, and its place in evolutionary biology. A number of epidemiological studies link small size at birth, assumed to be a consequence of constrained prenatal energy availability, with adverse effects on the risk of chronic diseases later in life. The cluster of chronic diseases associated with the metabolic syndrome and alterations of glucose metabolism are particularly implicated. Recent evidence suggests that epigenetic modification of gene expression affecting the hypothalamic-pituitary-adrenal (HPA) axis may be involved in these effects. In animal studies epigenetic alteration of HPA axis activity and responsiveness is associated with changes in adult behaviour and stress responsiveness. The potential for similar effects to contribute to psychological and psychiatric outcomes in humans has been explored in a number of contexts, including famine exposure, observed covariance with birth weight, and prenatal dexamethasone treatment of fetuses at risk of congenital adrenal hyperplasia. While fetal programming effects have now been widely demonstrated across species and human populations, the adaptive significance of these effects is still a matter of debate. Copyright © 2010 John Wiley & Sons, Ltd. [source]


Genetic and epigenetic alterations of the KLF6 gene in hepatocellular carcinoma

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2006
Jaehwi Song
Abstract Background and Aim:, Kruppel-like factor 6 (KLF6) is a zinc finger tumor suppressor gene that is frequently mutated in several human cancers and is broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. The aim of this study was to elucidate the potential etiological role of KLF6 in the development of hepatocellular carcinoma (HCC) in Korea. Methods:, The gene mutation, allelic loss, and methylation status of the KLF6 gene was analyzed in a series of 85 Korean patients: 21 with dysplastic nodules and 85 with HCC. Results:, No somatic mutations were observed in the patients with dysplastic nodules or with HCC. Allelic loss was found in five (6.8%) of 73 informative HCC tissues. Three of the five patients with allelic loss had HCC with hepatitis B virus infection and cirrhosis, and the remaining two had no viral infection and a non-specific background. In methylation analysis, unmethylated and methylated DNAs of the KLF6 gene were amplified in all corresponding non-neoplastic liver tissues. Only one HCC tissue showed methylated DNA without unmethylated DNA. Conclusions:, The results suggest that genetic and epigenetic alteration of KLF6 may play a minor role in the development of HCC. [source]


Hypermethylation of E-cadherin is an independent predictor of improved survival in head and neck squamous cell carcinoma,

CANCER, Issue 7 2008
Carmen J. Marsit PhD
Abstract BACKGROUND. The loss of E-cadherin (ECAD) protein expression has been linked to aggressive head and neck squamous cell carcinoma (HNSCC). Promoter hypermethylation of the cadherin 1, type 1 (CDH1) gene (encoding ECAD) is 1 mechanism by which this protein can be inactivated, although this epigenetic alteration of the gene has not been linked conclusively to poorer patient outcome and, in fact, may be associated with better patient prognosis. METHODS. The authors investigated the prevalence of CDH1 promoter hypermethylation in a population-based case series of 340 primary HNSCC tumors using methylation-specific polymerase chain reaction. They also studied the association between CDH1 hypermethylation and patient demographic characteristics using multivariate analysis and examined the impact of CDH1 hypermethylation on patient survival using both univariate and multivariate methods. RESULTS. Hypermethylation of CDH1 was significantly more prevalent (P < .03) among individuals with a low smoking history independent of whether they were seropositive for human papillomavirus type 16 (HPV-16). Patients who had tumors with CDH1 hypermethylation had significantly better overall survival compared with patients who had tumors without hypermethylation (P < .02; log-rank test). This effect was independent of HPV-16 status and demonstrated a significant hazard ratio of 0.5 (95% confidence interval, 0.3-0.9) in a model that controlled for HPV-16 serology, age, sex, and tumor stage. CONCLUSIONS. The current results suggested that hypermethylation of CDH1 occurs more commonly in patients with HNSCC who are low smokers, suggesting that an additional factor may be driving this epigenetic alteration. Clinically, CDH1 hypermethylation may hold powerful prognostic potential in addition to that observed with HPV serology, and the authors concluded that it should be pursued in additional studies. Cancer 2008. © 2008 American Cancer Society. [source]


MiR-221 and MiR-222 alterations in sporadic ovarian carcinoma: Relationship to CDKN1B, CDKNIC and overall survival

GENES, CHROMOSOMES AND CANCER, Issue 7 2010
Kaitlyn Wurz
MicroRNAs are often aberrantly expressed in human neoplasms and are postulated to play a role in neoplastic initiation and progression. miR-221 and miR-222 negatively regulate expression of CDKN1B (p27) and CDKN1C (p57), two cell cycle regulators expressed in ovarian surface epithelium and down-regulated in ovarian carcinomas. We characterized miR-221 and miR-222 expression in 49 sporadic high grade ovarian carcinomas and determined whether somatic mutation or epigenetic alterations explained the differences in expression of these miRNAs. We correlated these findings with protein expression of CDKN1B and CDKN1C as assessed by immunohistochemistry. Expression of miR-221 and miR-222 were closely correlated with each other (P = 0.0001). Interestingly, a lower ratio of miR-221 to miR-222 expression was significantly correlated with worse overall survival (P = 0.01) and remained a significant predictor of overall survival in multivariate analysis using the covariate adequacy of surgical cytoreduction (P = 0.03). Higher miR-222 and miR-221 expression were significantly associated with decreased CDKN1C expression (P = 0.009 and 0.01). In contrast, CDKN1B expression was not associated with miR-221 or miR-222 expression. Neither somatic mutations nor methylation of the studied region explained the alterations in miR-221 and miR-222 expression in most carcinomas. © 2010 Wiley-Liss, Inc. [source]


The MLH1 ,93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer

GENES, CHROMOSOMES AND CANCER, Issue 10 2008
Wade S. Samowitz
The MLH1 ,93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the ,93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The ,93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 ,93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 ,93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway. © 2008 Wiley-Liss, Inc. [source]


Down-regulation of ATBF1 is a major inactivating mechanism in hepatocellular carcinoma

HISTOPATHOLOGY, Issue 5 2008
C J Kim
Aims:, ,-Fetoprotein (AFP) is frequently detected in hepatocellular carcinomas (HCCs) and AT motif binding factor 1 (ATBF1) down-regulates AFP gene expression in hepatic cells. The ATBF1 gene also inhibits cell growth and differentiation, and altered gene expression is associated with malignant transformation. The aim was to investigate the potential role of the ATBF1 gene in HCCs. Methods and results:, Somatic mutations, allelic loss and hypermethylation of the ATBF1 gene were analysed in 76 sporadic HCCs. The level of ATBF-1 mRNA expression was analysed using quantitative real-time reverse transcriptase-polymerase chain reaction. Genetic studies of the ATBF1 gene revealed absence of somatic mutation in the hotspot region and 15 (25%) of 60 informative cases showed allelic loss at the ATBF1 locus. Hypermethylation in the intron 1 region of the ATBF1 gene was detected in only one case. Interestingly, ATBF1 mRNA expression in HCCs was significantly reduced in 55 (72.4%) samples compared with the corresponding surrounding liver tissues. Reduced expression was not statistically associated with clinicopathological parameters including stage, histological grade, infective virus type, and serum ,-fetoprotein level. Conclusions:, The ATBF1 gene may contribute to the development of HCCs via transcriptional down-regulation of mRNA expression, but not by genetic or epigenetic alterations. [source]


Reduced expression of MYO18B, a candidate tumor-suppressor gene on chromosome arm 22q, in ovarian cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2004
Nozomu Yanaihara
Abstract Allelic imbalance on chromosome arm 22q has been detected in 50,70% of ovarian cancers, suggesting the presence of a tumor-suppressor gene on this chromosome arm that is involved in ovarian carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, which is deleted, mutated and hypermethylated in approximately 50% of lung cancers. In our study, we analyzed genetic and epigenetic alterations of the MYO18B gene in ovarian cancers. Missense MYO18B mutations were detected in 1 of 4 (25%) ovarian cancer cell lines and in 1 of 17 (5.9%) primary ovarian cancers. MYO18B expression was reduced in all 4 ovarian cancer cell lines and in 12 of 17 (71%) of primary ovarian cancers. MYO18B expression was restored by treatment with 5-aza-2,-deoxycytidine and/or trichostatin A in 3 of 4 cell lines with reduced MYO18B expression, and hypermethylation of the promoter CpG island for MYO18B was observed in 2 of these 3 cell lines. Its hypermethylation was also observed in 2 of 15 (13%) primary ovarian cancers. Thus, it was indicated that MYO18B expression is reduced in a considerable fraction of ovarian cancers by several mechanisms, including hypermethylation, while the MYO18B gene is mutated in a small subset of ovarian cancers. The present results suggest that MYO18B alterations, including both epigenetic and genetic alterations, play an important role in ovarian carcinogenesis. © 2004 Wiley-Liss, Inc. [source]


Chromosome-mediated alterations of the MYC gene in human cancer

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2002
N. C. Popescu
Abstract The step-wise accumulation of genetic and epigenetic alterations in cancer development includes chromosome rearrangements and viral integration-mediated genetic alterations that frequently involve proto-oncogenes. Protooncogenes deregulation lead to unlimited, self-sufficient cell growth and ultimately generates invasive and destructive tumors. C-MYC gene, the cellular homologue of the avian myelocitic leukemia virus, is implicated in a large number of human solid tumors, leukemias and lymphomas as well as in a variety of animal neoplasias. Deregulated MYC expression is a common denominator in cancer. Chromosomal rearrangements and integration of oncogenic viruses frequently target MYC locus, causing structural or functional alterations of the gene. In this article, we illustrate how genomic rearrangements and viruses integration affect MYC locus in certain human lymphomas and solid tumors. [source]


Elevated expression of TMEM205, a hypothetical membrane protein, is associated with cisplatin resistance

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010
Ding-Wu Shen
Development of cisplatin resistance in cancer cells appears to be a consequence of multiple epigenetic alterations in genes involved in DNA damage repair, proto-oncogenes, apoptosis, transporters, transcription factors, etc. In this study, we found that expression of the hypothetical transmembrane protein TMEM205 (previously known as MBC3205) is associated with cisplatin resistance. TMEM205 was first detected by functional cloning from a retroviral cDNA library made from human cisplatin-resistant (CP-r) cells. TMEM205 is predicted to be a transmembrane protein, but its expression, localization, and function have not previously been investigated. A polyclonal antibody directed to the TMEM205 protein was raised in our laboratory. Using this antibody, it was demonstrated that this protein is located at the cell surface. Its expression is increased in our cisplatin-selected CP-r cell lines, as demonstrated by immunoblotting, confocal examination, and immuno-electron microscopy. Stable transfection of the TMEM205 gene confers resistance to cisplatin by approximately 2.5-fold. Uptake assays with Alexa Fluor-cisplatin showed reduced accumulation in CP-r KB-CP.3 and KB-CP.5 cells, and in TMEM205-transfected cells. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver, pancreas, and adrenal glands. These results indicate that a novel mechanism for cisplatin resistance is mediated by TMEM205, and also suggest that overexpression of TMEM205 in CP-r cells may be valuable as a biomarker or target in cancer chemotherapy. J. Cell. Physiol. 225: 822,828, 2010. © 2010 Wiley-Liss, Inc. [source]


Genetic and epigenetic alterations of the KLF6 gene in hepatocellular carcinoma

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2006
Jaehwi Song
Abstract Background and Aim:, Kruppel-like factor 6 (KLF6) is a zinc finger tumor suppressor gene that is frequently mutated in several human cancers and is broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. The aim of this study was to elucidate the potential etiological role of KLF6 in the development of hepatocellular carcinoma (HCC) in Korea. Methods:, The gene mutation, allelic loss, and methylation status of the KLF6 gene was analyzed in a series of 85 Korean patients: 21 with dysplastic nodules and 85 with HCC. Results:, No somatic mutations were observed in the patients with dysplastic nodules or with HCC. Allelic loss was found in five (6.8%) of 73 informative HCC tissues. Three of the five patients with allelic loss had HCC with hepatitis B virus infection and cirrhosis, and the remaining two had no viral infection and a non-specific background. In methylation analysis, unmethylated and methylated DNAs of the KLF6 gene were amplified in all corresponding non-neoplastic liver tissues. Only one HCC tissue showed methylated DNA without unmethylated DNA. Conclusions:, The results suggest that genetic and epigenetic alteration of KLF6 may play a minor role in the development of HCC. [source]


New light on the biology and developmental potential of haematopoietic stem cells and progenitor cells

JOURNAL OF INTERNAL MEDICINE, Issue 4 2009
M. Sigvardsson
Abstract. Even though stem cells have been identified in several tissues, one of the best understood somatic stem cells is the bone marrow residing haematopoietic stem cell (HSC). These cells are able to generate all types of blood cells found in the periphery over the lifetime of an animal, making them one of the most profound examples of tissue-restricted stem cells. HSC therapy also represents one of the absolutely most successful cell-based therapies applied both in the treatment of haematological disorders and cancer. However, to fully explore the clinical potential of HSCs we need to understand the molecular regulation of cell maturation and lineage commitment. The extensive research effort invested in this area has resulted in a rapid development of the understanding of the relationship between different blood cell lineages and increased understanding for how a balanced composition of blood cells can be generated. In this review, several of the basic features of HSCs, as well as their multipotent and lineage-restricted offspring, are addressed, providing a current view of the haematopoietic development tree. Some of the basic mechanisms believed to be involved in lineage restriction events including activities of permissive and instructive external signals are also discussed, besides transcription factor networks and epigenetic alterations to provide an up-to-date view of early haematopoiesis. [source]


Hypermethylation status of APC inversely correlates with the presence of submucosal invasion in laterally spreading colorectal tumors

MOLECULAR CARCINOGENESIS, Issue 1 2008
Kazuo Hashimoto
Abstract Little is known about epigenetic alterations in laterally spreading colorectal tumors (LSTs). The goal of the present study was to elucidate the epigenetic background of LSTs and compare the methylation status of DNA CpG islands (CGIs) with clinicopathologic features. Methylation of MINT1, MINT2, MINT31, p16, O6 -methylguanine-DNA methyltransferase (MGMT), adenomatous polyposis coli (APC), and human MutL homologue 1 (hMLH1) in 42 LSTs was assessed by methylation-specific polymerase chain reaction (MSP) and compared with clinicopathologic parameters. The frequency of hypermethylation was 12.5% (4/32) for MINT1, 40.0% (16/40) for MINT2, 25.0% (10/40) for MINT31, 25.7% (9/35) for p16, 7.7% (3/39) for hMLH1, 26.5% (9/34) for MGMT, and 35.9% (14/39) for APC. APC methylation was inversely associated with submucosal invasion (P,=,0.034), which was not found in any of 14 LST cases with APC methylation, whereas submucosal invasion was present in 8 of 25 (32.0%) cases without APC methylation. These data suggest that hypermethylation of APC could be a predictive marker for the absence of submucosal invasion of LSTs. © 2007 Wiley-Liss, Inc. [source]


Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis

MOLECULAR CARCINOGENESIS, Issue 3 2007
Volodymyr P. Tryndyak
Abstract Tamoxifen, a nonsteroidal anti-estrogen, is a potent genotoxic hepatocarcinogen in rats, with both tumor initiating and promoting properties. Recently it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations and these induced epigenetic changes may play important mechanistic role in carcinogenesis. In the present study, we investigated the role of tamoxifen-induced epigenetic changes in hepatocarcinogenic process. The results of the study showed that exposure of female F344 rats to tamoxifen resulted in progressive loss of CpG methylation in regulatory sequences of long interspersed nucleotide elements (LINE-1) and prominent increase in expression of LINE-1 elements and c- myc proto-oncogene. The accumulation of tamoxifen-induced DNA lesions was accompanied by the decreased level of Rad51, Ku70, and DNA polymerase , (Pol,) proteins that play a crucial role in maintenance of genomic stability. Furthermore, feeding rats with tamoxifen-containing diet led to increased regenerative cell proliferation, as indicated by the increased level of Ki-67 and proliferating cell nuclear antigen (PCNA) proteins. These data indicate that exposure of animals to genotoxic hepatocarcinogen tamoxifen led to early phenotypical alterations in livers characterized by emergence of epigenetically reprogrammed cells with a specific cancer-related epigenetic phenotype prior to tumor formation. © 2006 Wiley-Liss, Inc. [source]


Molecular characteristics of eight gastric cancer cell lines established in Japan

PATHOLOGY INTERNATIONAL, Issue 10 2000
Hiroshi Yokozaki
Molecular characterization of eight gastric cancer cell lines established in Japan are summarized according to the genetic and epigenetic alterations and growth factor status. TMK-1 poorly differentiated adenocarcinoma cell line harbors mutant p53 tumor suppressor gene and rearrangement of p15MTS2. MKN-1 adenosquamous carcinoma line with mutant p53 reveals silencing of E-cadherin by promoter CpG hypermethylation. MKN-7 well-differentiated adenocarcinoma cell line has amplification of c- erbB2 oncogene and cyclin E gene. MKN-28 well-differentiated adenocarcinoma cell line reveals mutations in p53 and APC tumor suppressor genes and silencing of CD44. The MKN-45 poorly differentiated adenocarcinoma cell line with wild-type p53 is characterized by homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplification of c-met oncogene and promoter mutation of E-cadherin. MKN-74 derived from moderately differentiated tubular adenocarcinoma has wild-type p53. KATO-III signet ring cell carcinoma line has genomic deletion of p53, amplification of K- sam and c- met oncogene and mutation of E-cadherin. HSC-39 signet ring cell carcinoma cell line harboring p53 missense mutation has homozygous deletion of p16CDKN2/MTS1/INK4A and p15MTS2, amplifications of c- myc, c- met, K- sam and CD44 gene and mutation in , -catenin gene. [source]


REVIEW ARTICLE: How to make a melanoma: what do we know of the primary clonal events?

PIGMENT CELL & MELANOMA RESEARCH, Issue 1 2008
Dorothy C. Bennett
Summary Rapid advances have been made in our knowledge of the commonest genetic and epigenetic alterations found in human sporadic melanomas. Valuable recent contributions came from analyses of gene copy number by comparative genome hybridization, and from large-scale gene expression profiling. All of the commonest affected genes encode regulatory components. Loci with established importance in melanoma, like CDKN2A, BRAF and PTEN, have been joined by some less familiar genes including transcription factor sequences TBX2 and STK11 (LKB). This knowledge is reviewed in relation to the cellular signaling pathways affected by these molecules, their biological outcomes, and the implications as to what changes are required overall to generate a melanoma. The data support a model in which genesis of melanoma requires changes that (1) initiate clonal expansion, (2) overcome cell senescence, and (3) reduce apoptosis. [source]


REVIEW ARTICLE: Epigenetics in the Placenta

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009
Matthew A. Maccani
Epigenetics is focused on understanding the control of gene expression beyond what is encoded in the sequence of DNA. Central to growing interest in the field is the hope that more can be learned about the epigenetic regulatory mechanisms underlying processes of human development and disease. Researchers have begun to examine epigenetic alterations , such as changes in promoter DNA methylation, genomic imprinting, and expression of miRNA , to learn more about epigenetic regulation in the placenta, an organ whose proper development and function are crucial to the health, growth, and survival of the developing fetus. A number of studies are now making important links between alterations to appropriate epigenetic regulation in the placenta and diseases of gestation and early life. In addition, these studies are adding important insight into our understanding of trophoblast biology and differentiation as well as placental immunology. Examining epigenetic alterations in the placenta will prove especially important in the search for biomarkers of exposure, pathology, and disease risk and can provide critical insights into the biology of development and pathogenesis of disease. Thus, epigenetic alterations may aid in disease diagnosis and prognosis as well as in targeting new treatment and prevention strategies. [source]


Epigenetic changes in cancer,

APMIS, Issue 10 2007
KIRSTEN GRØNBÆK
A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. Basically, this process is directed by changes in two different classes of genes: Tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. Since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. Cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. Epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in carcinogenesis. These epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the DNA is wrapped, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself. Methylation of clusters of CpGs called "CpG-islands" in the promoters of genes has been associated with heritable gene silencing. The present review will focus on how disruption of the epigenome can contribute to cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. Treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. Accordingly, in the clinical setting, DNA methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic therapy has recently been approved by the United States Food and Drug Administration (US FDA) for use in the treatment of myelodysplastic syndrome (MDS) and primary cutaneous T-cell lymphoma (CTCL). [source]


Genetic and epigenetic analysis of the KLF4 gene in gastric cancer,

APMIS, Issue 7 2007
YONG GU CHO
KLF4, which is also known as the gut-enriched Kruppel-like factor, plays important roles during the proliferation and differentiation of gastrointestinal epithelial cells. A loss of KLF4 expression has been observed in human tumors, particularly in the gastrointestinal tract. In this study, the molecular basis of the KLF4 inactivation in gastric cancer was investigated by analyzing the somatic mutation, the allelic loss with two microsatellite markers, D9S53 and D9S105, and hypermethylation of the KLF4 gene in 47 gastric adenomas and 81 gastric adenocarcinomas. Mutational analysis revealed one mutation of the KLF4 gene in a diffuse-type advanced gastric adenocarcinoma, but not in the gastric adenoma. This mutation was a somatic missense mutation, GGG,AGG (Gly,Arg) at codon 107 in exon 3, which encodes a transcriptional activation domain of the protein. An allelic loss was found in 7 (22.6%) of the 31 informative gastric adenoma cases and 15 (31.3%) of the 48 informative cancer cases at one or both markers. In addition, promoter hypermethylation of the KLF4 gene was observed in only two gastric cancers. These results suggest that genetic and epigenetic alterations of the KLF4 gene might play a minor role in gastric carcinogenesis. [source]


Exposure of human peripheral blood lymphocytes to electromagnetic fields associated with cellular phones leads to chromosomal instability

BIOELECTROMAGNETICS, Issue 2 2003
Maya Mashevich
Abstract Whether exposure to radiation emitted from cellular phones poses a health hazard is at the focus of current debate. We have examined whether in vitro exposure of human peripheral blood lymphocytes (PBL) to continuous 830 MHz electromagnetic fields causes losses and gains of chromosomes (aneuploidy), a major "somatic mutation" leading to genomic instability and thereby to cancer. PBL were irradiated at different average absorption rates (SAR) in the range of 1.6,8.8 W/kg for 72 hr in an exposure system based on a parallel plate resonator at temperatures ranging from 34.5,37.5 °C. The averaged SAR and its distribution in the exposed tissue culture flask were determined by combining measurements and numerical analysis based on a finite element simulation code. A linear increase in chromosome 17 aneuploidy was observed as a function of the SAR value, demonstrating that this radiation has a genotoxic effect. The SAR dependent aneuploidy was accompanied by an abnormal mode of replication of the chromosome 17 region engaged in segregation (repetitive DNA arrays associated with the centromere), suggesting that epigenetic alterations are involved in the SAR dependent genetic toxicity. Control experiments (i.e., without any RF radiation) carried out in the temperature range of 34.5,38.5 °C showed that elevated temperature is not associated with either the genetic or epigenetic alterations observed following RF radiation,the increased levels of aneuploidy and the modification in replication of the centromeric DNA arrays. These findings indicate that the genotoxic effect of the electromagnetic radiation is elicited via a non-thermal pathway. Moreover, the fact that aneuploidy is a phenomenon known to increase the risk for cancer, should be taken into consideration in future evaluation of exposure guidelines. Bioelectromagnetics 24:82,90, 2003. © 2003 Wiley-Liss, Inc. [source]


Genetic and epigenetic alterations in the differential diagnosis of malignant melanoma and spitzoid lesion

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2007
M. Takata
Summary Background, The histopathological differentiation of malignant melanoma and Spitz naevus often presents diagnostic problems. Objectives, We aimed to find out applicable diagnostic parameters other than routine pathology. Methods, The cases included conventional melanomas and Spitz naevi as well as atypical spitzoid lesions that had posed diagnostic difficulties. We examined hotspots of mutation in the BRAF, NRAS and HRAS genes by polymerase chain reaction-based direct sequencing. We also analysed DNA copy number aberrations and the methylation of CpG sequences in several cancer-related genes by utilizing a novel methylation-specific multiplex ligation-dependent probe amplification method. Results, Twenty three of 24 conventional melanomas showed at least one of the genetic and epigenetic alterations examined, although one acral melanoma did not show any alteration. By sharp contrast, 12 Spitz naevi with an unambiguous histopathology showed no or few chromosomal aberrations, no oncogene mutations and no methylation of CpG sequences. Of the 16 ambiguous spitzoid lesions, most of which were designated atypical Spitz tumour by one of the authors, all but one showed no mutations, no methylations and few copy number aberrations. However, three tumours showed copy number loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), an alteration observed frequently in melanomas but not found in conventional Spitz naevi. These results show that, although most atypical Spitz tumours do not differ from conventional Spitz naevi showing virtually no genetic and epigenetic aberrations, some cases may have chromosomal aberrations that include copy number loss of the CDKN2A gene. Conclusions, Genetic and epigenetic analyses may be useful as an additional diagnostic tool to distinguish between melanoma and Spitz naevus, and may help to define subgroups in atypical Spitz tumours. [source]


The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history

CANCER, Issue 15 2009
A target for risk diagnosis, prevention of esophageal cancers
Abstract BACKGROUND: Esophageal squamous cell carcinomas (ESCCs) tend to have multiple primary lesions, and it is believed that they arise from background mucosae with accumulation of genetic/epigenetic alterations. In this study, the objective was to elucidate the effects of smoking and drinking on the accumulation of epigenetic alterations in background mucosae. METHODS: Genes that are silenced in human ESCCs were searched for by treating 3 ESCC cell lines with the demethylating agent, 5-aza-2,-deoxycytidine and performing oligonucleotide microarrays. Methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction analysis of 60 ESCCs and their corresponding background mucosae. RESULTS: Forty-seven genes were identified as methylation-silenced in at least 1 of the 3 ESCC cell lines, and 14 of those genes (claudin 6 [CLDN6]; G protein-coupled receptor 158 [GPR158]; homeobox A9 [HOXA9]; metallothionein 1M [MT1M]; neurofilament, heavy polypeptide 200 kDa [NEFH]; plakophilin 1 [PKP1]; protein phosphatase 1, regulatory [inhibitor] subunit 14A [PPP1R14A]; pyrin domain and caspase recruitment domain containing [PYCARD]; R-spondin family, member 4 [RSPO4]; testis-specific protein, Y-encoded,like 5 [TSPYL5]; ubiquitin carboxyl-terminal esterase L1 [UCHL1]; zinc-finger protein 42 homolog [ZFP42]; zinc-finger protein interacting with K protein 1 homolog [ZIK1]; and zinc-finger and SCAN domain containing 18 [ZSCAN18]) were used as markers. In the background mucosae, methylation levels of 5 genes (HOXA9, MT1M, NEFH, RSPO4, and UCHL1) had significant correlations with smoking duration (, = .268; P = .044; , = .405; P = .002; , = .285; P = .032; , = .300; P = .024; and , = .437; P = .001, respectively). In contrast, an inverse correlation between PYCARD methylation levels and alcohol intake was observed (, = ,.334, P = .025) among individuals with the inactive aldehyde dehydrogenase 2 (ALDH2) genotype. CONCLUSIONS: The current results suggested that ESCCs developed from an epigenetic field for cancerization, which was induced by exposure to carcinogenic factors, such as tobacco smoking. The epigenetic field defect will be a novel target for risk diagnosis and prevention of ESCCs. Cancer 2009. © 2009 American Cancer Society. [source]


Cancer stem cells and chemoradiation resistance

CANCER SCIENCE, Issue 10 2008
Hideshi Ishii
Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multistepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by antiapoptotic signaling. CSCs mimic normal adult stem cells by demonstrating resistance to toxic injuries and chemoradiation therapy. Moreover, they might be responsible for tumor relapse following apparent beneficial treatments. Compared with hematopoietic malignancies, conventional therapy regimes in solid tumors have improved the overall survival marginally, illustrating the profound impact of treatment resistance. This implies that the present therapies, which follow total elimination of rapidly dividing and differentiated tumor cells, need to be modified to target CSCs that repopulate the tumor. In this review article, we report on recent findings regarding the involvement of CSCs in chemoradiation resistance and provide new insights into their therapeutic implications in cancer. (Cancer Sci 2008; 99: 1871,1877) [source]


Genetic and epigenetic changes in aberrant crypt foci and serrated polyps

CANCER SCIENCE, Issue 6 2008
Yutaka Suehiro
Aberrant crypt foci (ACF) in colorectal mucosa are the earliest known morphological precursors to colorectal cancer and can be subclassified as dysplastic, heteroplastic (non-dysplastic), and mixed types. Serrated adenoma (SA) is a polyp with serrated architecture and dysplasia, and can be subclassified as traditional SA or sessile SA. Sessile SA is thought to be preneoplastic and differs from most lesions in the traditional SA category because of their flat morphology and general lack of cytological dysplasia. Serrated polyps include hyperplastic polyps (HP), SA, and admixed hyperplastic-adenomatous polyps and are considered a morphological continuum encompassing heteroplastic ACF, HP, admixed hyperplastic-adenomatous polyps, and SA. Recent studies have uncovered other developmental pathways including a heteroplastic ACF-HP/SA-carcinoma sequence and a heteroplastic ACF,adenoma,carcinoma sequence. Heteroplastic ACF histopathologically resemble HP and SA. Sporadic HP are usually present in the left colon, are small, and are considered benign. However, adenocarcinoma arising in the setting of colorectal HP or SA, especially in patients with hyperplastic polyposis, has been described. The relationship between heteroplastic ACF, HP, and colorectal cancer is less certain than that of dysplastic ACF. Here, we discuss the current understanding of genetic and epigenetic alterations in the development of colorectal cancer. Our goal is to provide a conceptual framework for understanding the heteroplastic ACF,HP/SA,carcinoma sequence. (Cancer Sci 2008; 99: 1071,1076) [source]


Genetic and epigenetic factors involved in B-cell lymphomagenesis

CANCER SCIENCE, Issue 9 2004
Masao Seto
Malignant lymphomas have been classified by the WHO into disease categories based not only on histological features, but also on cell surface markers, cytogenetic and clinical features. It is known that chromosome translocation plays an important role in lymphoma development, but it is not entirely clear yet why a given type of chromosome translocation is associated with a specific type of lymphoma. This review deals with molecular mechanisms of B-cell lymphoma development in association with chromosome translocations. The outcome of chromosome translo-cations can be categorized into three factors: enhancement of proliferation, inhibition of differentiation and anti-apoptotic activity. It is well known that chromosome translocation by itself cannot cause cells to become malignant because it is only one of the growth advantages leading to malignancy, while additional genetic and epigenetic alterations are required for cells to become fully malignant. Mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach are unique in that a majority can be cured by Helicobacter pylori eradication, although 20 to 30% remain resistant. Others as well as we have demonstrated that the presence of the API2-MALT1 chimeric gene correlates well with resistance to H. pylori eradication treatment. These characteristics have led to the speculation that the classification of MALT lymphoma falls somewhere between tumor and inflammation. Although MALT lymphoma seems to have unique features in comparison with other types of B-cell lymphomas, it shares common molecular mechanisms with B-cell lymphoma development. [source]


The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history

CANCER, Issue 15 2009
A target for risk diagnosis, prevention of esophageal cancers
Abstract BACKGROUND: Esophageal squamous cell carcinomas (ESCCs) tend to have multiple primary lesions, and it is believed that they arise from background mucosae with accumulation of genetic/epigenetic alterations. In this study, the objective was to elucidate the effects of smoking and drinking on the accumulation of epigenetic alterations in background mucosae. METHODS: Genes that are silenced in human ESCCs were searched for by treating 3 ESCC cell lines with the demethylating agent, 5-aza-2,-deoxycytidine and performing oligonucleotide microarrays. Methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction analysis of 60 ESCCs and their corresponding background mucosae. RESULTS: Forty-seven genes were identified as methylation-silenced in at least 1 of the 3 ESCC cell lines, and 14 of those genes (claudin 6 [CLDN6]; G protein-coupled receptor 158 [GPR158]; homeobox A9 [HOXA9]; metallothionein 1M [MT1M]; neurofilament, heavy polypeptide 200 kDa [NEFH]; plakophilin 1 [PKP1]; protein phosphatase 1, regulatory [inhibitor] subunit 14A [PPP1R14A]; pyrin domain and caspase recruitment domain containing [PYCARD]; R-spondin family, member 4 [RSPO4]; testis-specific protein, Y-encoded,like 5 [TSPYL5]; ubiquitin carboxyl-terminal esterase L1 [UCHL1]; zinc-finger protein 42 homolog [ZFP42]; zinc-finger protein interacting with K protein 1 homolog [ZIK1]; and zinc-finger and SCAN domain containing 18 [ZSCAN18]) were used as markers. In the background mucosae, methylation levels of 5 genes (HOXA9, MT1M, NEFH, RSPO4, and UCHL1) had significant correlations with smoking duration (, = .268; P = .044; , = .405; P = .002; , = .285; P = .032; , = .300; P = .024; and , = .437; P = .001, respectively). In contrast, an inverse correlation between PYCARD methylation levels and alcohol intake was observed (, = ,.334, P = .025) among individuals with the inactive aldehyde dehydrogenase 2 (ALDH2) genotype. CONCLUSIONS: The current results suggested that ESCCs developed from an epigenetic field for cancerization, which was induced by exposure to carcinogenic factors, such as tobacco smoking. The epigenetic field defect will be a novel target for risk diagnosis and prevention of ESCCs. Cancer 2009. © 2009 American Cancer Society. [source]


Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells

CANCER SCIENCE, Issue 1 2010
Yoshitaka Sekido
Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16INK4a/p14ARF and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well-known oncogenes such as K-RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K),AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM. (Cancer Sci 2009) [source]