2,132
Views
65
CrossRef citations to date
0
Altmetric
Review

DNA methylation in endometrial cancer

&
Pages 491-498 | Received 02 Mar 2010, Accepted 21 May 2010, Published online: 16 Aug 2010

Abstract

Endometrial cancer is the most commonly diagnosed gynecological cancer, and it has been shown to be a complex disease driven by abnormal genetic, and epigenetic alterations, as well as environmental factors. Epigenetic changes resulting in aberrant gene expression are dynamic and modifiable features of many cancer types. A significant epigenetic change is aberrant DNA methylation. In this review, we review evidence on the role of aberrant DNA methylation, examining changes in relation to endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to endometrial cancer with the emphasis on the role of dietary/ lifestyle and environmental factors, as well as opportunities and challenges of DNA methylation in endometrial cancer management and prevention.

Introduction

Endometrial cancer is the most commonly diagnosed gynecological cancer. It is the 4th most common cancer for women, with 42,160 new cases and 7,780 deaths occurring in the United States in 2009.Citation1 Based on differences in clinicopathologic characteristics, there are two subtypes of endometrial carcinoma. Type I, endometrioid endometrial carcinoma, accounts for approximately 80% of cases, occurs frequently in pre- and peri-menopausal women, and is significantly related to a history of unopposed estrogen exposure or other hyperestrogenic risk factors. Type I tumors are usually well differentiated, and most patients present with early-stage of the disease and have a favorable prognosis. In contrast, type II, non-endometrioid endometrial carcinoma, is more common in older postmenopausal women, often poorly differentiated, and not associated with hyperestrogenic factors. Patients with type II tumors are more likely to have metastasis and are at high risk of relapse.Citation2 Type I tumors commonly have near-diploid karyotypes, microsatellite instability and mutations in PTEN, K-RAS and CTNNB1 (β-catenin) genes; whereas type II tumors are characterized more often by p53 mutation, overexpression of Her-2/neu and an aneuploid karyotype.Citation2

Although multiple risk factors, such as age, overweight/obesity and postmenopausal hormone therapy, have been identified, the understanding of the etiologies of the two subtypes of endometrial cancer continues to evolve. Similar to other cancer sites, endometrial cancer has been shown to be a complex disease driven by abnormal genetic, and epigenetic alterations, as well as environmental factors. As a common molecular alteration in human neoplasia, epigenetics is defined as heritable changes in gene expression without alteration of the nucleotide sequence.Citation3 Epigenetic changes are dynamic and modifiable upon treatment with pharmacological agents. In the last ten years, it has become increasingly apparent that epigenetic regulation of gene expression is at least as important to carcinogenesis as more studied genetic disruptions including aneuploidy, point mutations and variation in gene copy number, both gain or loss. While epigenetics refers to a broader class of changes, we focus here on the role of DNA methylation, a significant epigenetic change, examining those changes in relation to endometrial carcinogenesis. We report on recent advances in the understanding of the contribution of aberrant DNA methylation to endometrial cancer with the emphasis on the role of dietary/lifestyle and environmental factors, as well as opportunities and challenges of DNA methylation in endometrial cancer management and prevention.

Aberrant DNA Methylation in Endometrial Cancer

The best-known epigenetic event is aberrant DNA methylation. In humans, mediated by the three known active DNA cytosine methyltransferase (DNMT1, 3A and 3B),Citation4 a methyl group (-CH3) is covalently bonded to cytosine residues of the CpG dinucleotides, resulting in 5-methylcytosine. DNMT1 maintains attachment of methyl groups to hemimethylated DNA during replication, whereas DNMT3A and DNMT3B can catalyze de novo methylation of DNA.Citation5,Citation6 These enzymes cooperatively regulate the dynamic methylation of DNA. CpG dinucleotides are frequently clustered in CpG islands, regions of DNA rich in CpG sites (60–70%).Citation7,Citation8 These island are usually in or around the promoter regions and often unmethylated in normal tissue,Citation7,Citation8 and most CpG sites in the human genome are methylated.Citation9 DNA methylation is found in normal tissue and contributes to control of transcription,Citation10 affecting processes such as normal development,Citation11,Citation12 silencing of genes on the X-chromosome in femalesCitation10,Citation13 and gene imprinting.Citation14 Aberrant DNA methylation has been associated with most human tumors,Citation15,Citation16 as well as other non-neoplastic diseases and with aging.Citation17,Citation18

Decreased DNA methylation (hypomethylation) is an early event in carcinogenesis, and one of the first epigenetic alterations.Citation19 Hypomethylation can occur at normally methylated DNA sequences as repeated sequences, as well as both encoding regions and introns of genes.Citation15,Citation20 It is associated with early stage genetic instability and upregulation of gene expression.Citation20,Citation21 Another form of aberrant DNA methylation, hypermethylation of CpG islands in the promoter region of particular genes, appears to be significant in carcinogenesis for a number of tumor sites. Promoter hypermethylation is associated with gene silencing, and can affect carcinogenesis particularly when the affected gene is a tumor suppressor genes or other genes involved in the cell cycle, DNA mismatch repair, cell-to-cell interaction, steroid receptor, apoptosis and angiogenesis.Citation22 There is evidence that aberrant DNA methylation is an early and widespread alteration in endometrial tumorigenesis, which is implicated in loss of expression of a variety of critical genes. A recent study of methylation profile in endometrial tumorigenesis showed that, among 24 tumor suppressor genes, the number of promoter methylated loci increased in the progression from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia).Citation23 In addition, aberrant DNA methylation of some tumor suppressor genes was evident before endometrial carcinoma diagnosis in women with the DNA mismatch repair gene mutation.Citation23 This study provides important evidence into the timing and molecular alterations of the critical events in endometrial carcinogenesis, which may be useful to identify DNA methylation profile for early detection of endometrial cancer. In the following review, we summarize the genes that are frequently silenced by DNA methylation in endometrial cancer () and discuss how this mechanism may contribute to endometrial carcinogenesis.

Promoter Hypermethylation of Genes in Endometrial Cancer

DNA mismatch repair gene in endometrial cancer.

Germline mutations in DNA mismatch repair genes hMLH1, hMSH2, hMSH3, hMSH6 and hPMS2 have been identified in majority hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome and in associated familial endometrial cancer.Citation24 A significant characteristic of HNPCC is the presence of microsatellite instability (MSI), changes in the lengths of repetitive genetic loci.Citation24 MSI has also been observed to be present in approximately 20% of sporadic endometrial carcinomas,Citation25Citation30 while hMLH1 and hMSH2 mutations are rare (less than 10%) in sporadic endometrial cancers with the MSI+ phenotype.Citation31Citation34 However, reduced protein expression of hMLH1 and other mismatch repair genes is a common finding in endometrial cancers lacking detectable mutations.Citation31,Citation35Citation38 There is evidence that promoter methylation is associated with lack of expression of hMLH1 in human cancers and in mismatch repair-defective human tumor cell lines.Citation39Citation42 A strong association between hMLH1 promoter methylation and transcriptional silencing and MSI+ phenotype was also reported in sporadic endometrial cancer, particularly in the endometroid type.Citation27,Citation31,Citation38,Citation43Citation45 In addition, the demethylation of the hMLH1gene in several cell lines, including one endometrial carcinoma cell line, using the agent 5-aza-2′-deoxycytidine resulted in reaction of hMLH1expression and restoration of the activity of mismatch repair genes.Citation46 hMLH1 promoter methylation has also been shown to be an early event in the procession from normal endometrium to carcinoma, and as a feature of a subset of precursor lesion.Citation47Citation51 However, hMLH2 methylation is very rare (1.4% of 138 studied cases) in endometrial cancer.Citation44

Methylation of steroid receptor genes in endometrial cancer.

It is known that the endometrium is highly responsive to hormonal stimuli. The cyclic production of estrogen and progesterone during the menstrual cycle, and declining sex steroid hormone levels after menopause are directly correlated with endometrial proliferation and/or atrophic morphological changes. The majority of known risk factors for endometrial cancer are thought to be directly or indirectly related to exposure to hormones, particularly estrogen. A number of studies have evaluated the association of promoter methylation of the estrogen receptor (ER) and progesterone receptor (PR) genes in endometrial cancer.

The ER gene, located at chromosome 6q25.1, has a CpG island in its promoter and exon 1 regions. Reduced ER RNA and protein expression levels have been found in human endometrial cancer tissues and cell lines,Citation52,Citation53 while have not been consistently reported to be associated with aberrant promoter methylation of ER.Citation53Citation57 The expression of three isoforms of ERα (ERα-A, ERα-B and ERα-C) and ERβ genes in endometrial cancer cell lines was investigated by Sasaki et al.Citation53 They found no ERα-C expression, as well as restoration of the expression with 5-aza-2′-deoxycytidine treatment. They further found promoter methylation of ERα-C isoform in 94% of endometrial cancer tissues.Citation53 However, Shiozawa et al.Citation56 detected ER promoter methylation in only 24% of 25 endometrial cancer cases; methylation was correlated with ER-negative status of the tumors. Navari et al.Citation55 also did not find any association between loss of ER expression and de novo methylation of the ER gene. Moreover, neither ShiozawaCitation56 nor NavariCitation55 detected alterations in the methylation patterns of different ER isoforms. Although the specific role of the three ERα isoforms in endometrial cancer is still not clear, it was hypothesized that each isoform has a specific character due to the existence of elaborate mechanisms regulating estrogenic effects. Further studies investigating promoter methylation of ERα isoforms in endometrial cancer are needed.

The PR gene, located at chromosome 11q13, also has a CpG island in its first exon. The PR gene encodes two distinct subtypes, PR-A (94 kDa) and PR-B (114 kDa), with distinct functions.Citation58 Previous studies showed that the ratio of PR-A to PR-B expression is abnormal in endometrial cancer, leading to an inappropriate response to progesterone.Citation58,Citation59 Consistent with the transcriptional levels of the two PR isoforms, in one study, over 70% of the samples were promoter methylated for PR-B in endometrial cancer, primarily in tissues from type I cancers; however, PR-A was unmethylated in all cancer and normal endometrial samples.Citation60 It has been suggested that progesterone acts principally through PR-B to inhibit endometrial cancer cell invasiveness modulated by adhesion molecules.Citation61 Evidence from studies of endometrial cancer cell lines indicated that these changes may be the result of aberrant DNA methylation of these genes. Such cell culture studies have shown no PR-B expression, although PR-A expression was observed.Citation60 Other studies have shown a positive association between promoter hypermethylation of PR-B and reduced PR mRNA expression in these cancer cell lines;Citation62,Citation63 DNMT inhibitor 5-aza-2′-deoxycytidine, as well as histone deacetylase (HDAC) inhibitor trichostatin A, led to demethylation and restoration of PR expression.

Methylation of tumor suppressor genes in endometrial cancer.

Promoter hypermethylation of tumor suppressor genes is a major event in the origin of many cancers, and has been the focus of attention in the last decade. A number of studies established a list of tumor suppressor genes frequently hyper-methylated in endometrial cancer. The phosphatase and ten-sin homolog (PTEN, also known as MMAC1/TEP1) gene on chromosome 10q23.3, responsible for Cowden syndromeCitation64 and BannyanZonana syndrome,Citation65 encodes a dual-specificity phosphatase able to dephosphorylate both tyrosine phosphate and serine/threonine phosphate residues.Citation66 It is reported to be important for the inhibition of cell migration and spreading and focal adhesion.Citation66 Inactivation of PTEN has been observed in a number of human cancers, including endometrial cancer. PTEN mutations occur in to 26–80% of endometrial cancers, making it the most commonly known genetic alteration associated with this disease.Citation67,Citation68 Promoter hypermethylation, as the alternative mechanism of PTEN allelic inactivation, was first demonstrated as an occurrence in sporadic colorectal tumors with microsatellite instability, reported to be on the order of 19% of tumors.Citation69 A number of studies have also shown that PTEN promoter methylation in about 20% of sporadic type I endometrial carcinoma,Citation70Citation72 and that this methylation is significantly associated with metastatic disease and with MSI phenotype.Citation72 However, results from Zysman et al.Citation73 suggested that it is PTEN pseudogene, and not PTEN itself, which is predominantly methylated in endometrial cancer cell lines and in endometrial tumors. More studies with the ability to make distinction between promoter methylation of PTEN and its pseudogene are needed to understand better the mechanisms of PTEN inactivation in endometrial carcinogenesis.

Located on chromosome 9p21, the p16 gene encodes a cyclindependent kinase inhibitor, which can block the cell cycle and arrest the growth of deregulated cancer cells.Citation74 Loss of p16 expression resulting from homozygous deletion, mutation or promoter methylation is a common feature of many human cancers and of cancer cell lines. Promoter methylation of p16 gene has been observed in between 11% and 75% of sporadic endometrial cancers;Citation51,Citation75Citation78 however, other studies have reported much lower frequencies of p16 methylation.Citation50,Citation79Citation81 This variability may be a reflection of variation in the sensitivity of the assays used to assess p16 methylation, differences in primer design for the same assay, and differences in sample size or differences in the populations under study. Furthermore, there is limited and inconsistent data regarding the correlation between that p16 promoter hypermethylation and clinicopathological features of endometrial cancer. Although Wong et al.Citation75 reported that p16 promoter methylation was associated with advanced stage and poorer survival of endometrial cancer, no correlation was observed between promoter methylation of p16 and clinicpathological features and prognosis of endometrial cancer in another recent study.Citation76 In addition, some studies found that p16 gene inactivation but rare p16 methylation occurs in a subgroup of aggressive endometrial carcinomas with poor prognosis,Citation80,Citation81 which suggests that the molecular mechanisms of p16 inactivation in endometrial cancer remain unclear.

Another tumor suppressor gene, Ras-association domain gene family 1A (RASSF1A) is located at chromosome 3p21.3 and is known to induce cell cycle arrest through the Rb-mediated checkpoint by inhibiting the accumulation of cyclin D1.Citation82,Citation83 Alteration of this tumor suppressor gene is frequently found in tumors from a variety of sites.Citation82,Citation83 RASSF1A promoter methylation has been reported to occur in 33–85% of endometrial cancers and is associated with reduced expression of RASSF1A.Citation84Citation90 Arafa et al.Citation84 recently observed frequent hypermethylation of RASSF1A gene promoter (36%) in normal endometrium adjacent to endometrioid carcinoma, suggesting that RASSF1A promoter methylation is an early event in type I endometrial carcinogenesis. Hypermethylation of this gene has been found to be correlated with loss of heterozygosity (LOH); in a study of cervical cancer, 8 of 12 (67%) with hypermethylated RASSF1A gene showed concomitant LOH at 3p21.Citation91 LOH at 3p is a frequent occurrence in endometrial cancer.Citation92 Aberrant promoter methylation of RASSF1A gene combined with LOH at 3p may play a more important role in endometrial carcinogenesis. Moreover, promoter methylation of RASSF1A has also been inconsistently found to be associated with advanced stage, recurrence and survival for endometrial cancer.Citation86Citation89,Citation93 These inconsistent associations may be due to small sample size, different subtypes of endometrial cancer under study, and short follow-up period for recurrent and survival analyses.

Adenomatous polyposis coli (APC), a tumor suppressor gene, regulates β-catenin in the Wnt signaling pathway, and the aberrations in the Wnt pathway appear to impact the initiation and progression of several human cancers.Citation94,Citation95 Alterations in the APC gene or in the β-catenin gene may affect the Wnt pathway and are thought to be associated with endometrial carcinogenesis.Citation96,Citation97 However, mutations of the APC gene are not common events in endometrial cancers.Citation96,Citation98,Citation99 APC gene promoter methylation has been demonstrated in around 20–45% of endometrial cancers,Citation50,Citation78,Citation90,Citation93,Citation98Citation101 and more frequent APC promoter methylation in tumors with MSI than in those without MSI was reported in several studies.Citation98Citation100 No significant associations of APC promoter methylation with the cliniopathological factors or recurrence and distant metastases have been observed in endometrial cancers.Citation50,Citation78

β-catenin can complex with molecules including both APC and E-cadherin and is also involved in cell adhesion, together with E-cadherin, α-catenin and γ-catenin.Citation102 A few studies have evaluated promoter methylation of E-cadherin, a possible tumor suppressor gene, in endometrial cancer.Citation50,Citation99,Citation103,Citation104 Results of these studies have not been consistent. Sito et al.Citation104 reported that the aberrant methylation in promoter region of E-cadherin gene is associated with poor differentiation and myometrial invasion in endometrial carcinomas, suggesting a possible role of E-cadherin in endometrial cancer progression. However, no association between E-cadherin hypermethylation and clinicopathological or immunohistochemical features of endometrial cancer was found in other studies.Citation50,Citation99,Citation103 Pijnenborg et al.Citation99 did not find E-cadherin gene promoter methylation in the tested endometrial tumors, although the absence of E-cadherin expression was detected and found to be associated with the development of distant metastases.

Aberrant MGMT methylation in endometrial cancer.

O-6-methyguanine-DNA-methyltransferase (MGMT), a DNA repair gene, reverses DNA damage via alkylation by removing the methyl group from the O6-guanine and hence protects against DNA mutations. MGMT promoter methylation has been found for a number of cancer sites and precancerous lesions, including colorectal, gastric, lung and glioblastoma; however, it has only been examined in a few studies of endometrial cancer.Citation77,Citation84,Citation101,Citation105 Methylation of MGMT was detected in 48% of synchronous carcinomas of the uterine corpus and ovary;Citation77 however, low frequency or absence of MGMT promoter methylation in singly occurring endometrial cancer was reported in several other studies.Citation84,Citation101,Citation105

Methylation and inactivation of other genes in endometrial cancer.

Retinoic acid receptor (RAR) α, -β and -γ and retinoid X receptor are members of the intercellular receptor superfamily. The RARβ2 gene has been found to be silenced by promoter methylation in both type I endometrial cancers and endometrial hyperplasia,Citation84,Citation106 suggesting aberrant methylation of RARβ2 gene as an early epigenetic alteration of endometrial carcinogenesis. Other genes, such as cell cycle inhibitor gene 14-3-3σ,Citation107 paternally expressed gene 3 (PEG3) involved in apoptosis,Citation108 the detoxifying enzyme glutathione S-transferase P1 (GSTP1),Citation109 homeobox genes HOPX, HOXA10 and HOXA11,Citation110Citation112 RUNX3 tumor suppressor gene,Citation113 and metallothionein 1E gene (MT-1E),Citation114 have been found to be inactivated by aberrant methylation in promoter region in endometrial cancer; however, the impacts of promoter methylation of these genes on endometrial carcinogenesis have not been well known and need to be further investigated.

Difference in DNA methylation in type I and type II endometrial cancers.

There is evidence that type I and II endometrial cancers also contain distinct profiles of aberrant DNA methylation. Promoter hypermethylation of genes including MLH1, APC, MGMT, PTEN and RASSF1A is more frequently detected in type I than type II tumors.Citation72,Citation86,Citation98,Citation115 In addition, promoter hypermethylation of PR-B has been found as a mechanism of loss of PR-B expression in endometrial cancer; and tumors and cell lines applied in those studies included predominantly type I cancers,Citation60,Citation62 although PR negative is more common in type II cancer.Citation116 These findings suggest that promoter hypermethylation may play less of a role in the tumorigenesis of type II cancers.

Some recent studies investigated the expression levels of DNMT1 and DNMT3B in normal endometrium and type I and type II endometrial carcinomas. Compared to normal endometrium, expression levels of both DNMT1 and DNMT3B were significantly increased in type I cancers but downregulated in type II cancers.Citation86,Citation117 Although DNMT1 is known to function as a maintenance methyltraferase, there is evidence that DNMT1 and DNMT3B cooperatively catalyze de novo methylation.Citation6 The lower expression of DNMT1 and DNMT3B may result in global hypomethylation in type II endometrial cancers and contribute to histological differences. More studies are needed to characterize the aberrant DNA methylation profiles in type I and II cancers, to identify different mechanisms for different phenotypes, and to elucidate appropriate prevention approaches.

Environmental Factors, DNA Methylation and Endometrial Cancer

Epidemiology and experimental studies have found a number of agents in diet and environment involved the epigenetic alterations in the process of a variety of human cancers, including endometrial cancer. Those agents are considered “epigenetic carcinogens” (epimutagens).Citation118

Diet.

Diet is an important modifier of DNA methylation profile. The most studied and among the best understood is the relationship between micronutrients involved in one-carbon metabolism and DNA methylation.Citation119Citation121 Folate plays a central role in one carbon metabolism that provides a methyl group for a variety of biological process including methylation of DNA, RNA and protein, as well as the synthesis of purines and pyrimidines for DNA synthesis.Citation119Citation121 Vitamins B2, B6 and B12, the essential amino acid, methionine, are also involved in one carbon metabolism, potentially affecting genomic DNA methylation and synthesis and thereby causing dysregulation of gene expression.Citation119Citation121 Low levels of folate, vitamins B2, B6, B12 and methionine have been shown to be associated with cancer and cardiovascular disease risk.Citation122,Citation123 Deficiencies of methyl donor intake and excess alcohol consumption have been found to induce promoter hypermethylation and global hypomethylation in animal models.Citation124Citation126 However, there is limited evidence from epidemiological studies of different cancer sites that these nutrients intake affect DNA methylation;Citation127Citation131 and very little known for the potential effect of low level of methyl donor intake on endometrial DNA methylation. One concern with interpretation of these inconsistent findings is that each study examined methylation status of a limited number of genes, it cannot be ruled out that methyl donor intake may have impact on promoter methylation of other excluded genes. There is evidence that the folate status may be tissue specific,Citation121 which may explain at least in part the inconsistency of study results. Moreover, diet can also alter histone modification.Citation118 It is possible that diet may impact development of cancer through the mechanisms of both DNA methylation and other epigenetic alterations.

Phytoestrogens are naturally occurring compounds in many foods such as soy and soy products, and associated with reduced endometrial cancer risk in Asian populations and western vegetarian populations. Genistein, one of many phytoestrogens presented in soy, can inhibit cell growth, angiognesis and induces apoptosis in cancer cell lines and animal models;Citation132Citation134 and exhibit mixed estrogenic and anti-estrogenic properties.Citation135 The underlying molecular mechanisms for these effects of genistein are not well established, but recent studies suggest that genistein may regulate gene activity by modulating epigenetic events. While there are no data on this possible association for endometrial cancer, there is some evidence from other cancer sites that phytoestrogen intake may affect methylation. Day et al.Citation136 reported gene-specific increases in prostate DNA methylation patterns among mice treated with a diet high in genistein compared to mice on a control diet. Several studies also have shown that genistein, lignans, and other related soy isoflavones can reverse hypermethylation and reactivate the silenced genes, including RARβ2, p16, MGMT, GSTP1 and BTG3 genes, in esophageal, breast and renal cancer cell lines.Citation137Citation140 These in vitro data showed that genistein can have a dose-dependent inhibition of DNMTA and HDAC activities,Citation137 and increase active chromatin modifications near the transcription start site.Citation140 However, in a recent study conducted in healthy premenopausal women, promoter methylation of RARβ2 and CCND2 genes in mammary tissue was lower for women with low blood genistein and higher among those with higher circulating genistein.Citation141 These in vitro studies used higher concentrations of genistein than those found in women consuming soy products.Citation137,Citation141 Further studies are needed to evaluate the impact and potential mechanism of dietary phytoestrogens on DNA methylation in endometrial tissue, and identify the proper administration level of phytoestrogens recommended for chemoprevention of endometrial cancer.

Other lifestyle factors.

Physical activity has been shown to be associated with modestly reduced risk of endometrial cancer. A recent cross-sectional study in women without breast cancer found that both lifetime and recent physical activity were inversely related with promoter hypermethylation of APC gene in nonmalignant breast tissue.Citation142 No similar studies on endometrial cancer have been reported, but the finding for breast tissue suggests that the protective effect of physical activity on endometrium may be associated with epigenetic changes including DNA methylation.

External steroid hormones.

In the past several decades, external sources of steroid hormones, which influence cell proliferation and therefore the risk of endometrial cancer, have been widely used and contribute to endometrial cancer development, particularly type I tumors. Epigenetic events may play an important role in the physiological response to external steroid hormones and undergo continuous modification and alteration. Progestrone has been given in combination with estrogen in hormone therapy to prevent the increased risk of endometrial cancer associated with unopposed estrogen therapy. The use of combined oral contraceptives (COCs) has generally been seen to reduce the risk of endometrial cancer,Citation143Citation145 which may be due to the progestrone component of COCs. Recent studies showed that DNMT3A and DNMT3B in human endometrium are under the regulation of both progesterone and estrogen, suggesting DNA methylation may be influenced by sex steroid hormones.Citation146 It is possible the external progesterone mediates a protective effect on endometrium through impacting DNMT activities or downregulation of an epimutagen effect of estrogen by epigenetic modifications. However, more studies are needed to clarify the molecular mechanisms of external progestin on endometrium.

Conclusion

Recent developments in the field of epigenetics, especially studies of DNA methylation, have provided valuable insights for understanding the role of epigenetic alterations in normal cellular processes and abnormal changes leading to endometrial carcinogenesis. These new insights hold tremendous potential in the diagnosis, treatment and prevention of endometrial cancer.

There is accumulating evidence that DNA methylation changes may contribute to carcinogenesis in the endometrium, although evidence regarding these changes induced by dietary/lifestyle and environmental factors in endometrial cancer is quite limited. There is still much to explore regarding the target genes of aberrant methylation, how they contribute to the carcinogenic process and what factors affect that methylation. The emerging powerful technologiesCitation147 can be used to quickly identify DNA methylation profiles for different subtypes of endometrial cancer. In addition, epigenetic-epidemiological studies provide opportunities not only to study the contribution of epigenetics to endometrial cancer but to understand the joint impact of genetic, epigenetic and environmental exposures on the risk of endometrial cancer.

Figures and Tables

Table 1 Selected genes frequently silenced by DNA promoter methylation in endometrial carcinoma

Acknowledgement

This work was supported by the National Cancer Institute (R01CA 092040).

References

  • American Cancer Society. Cancer Facts and Figures 2009 2009; www.cancer.org
  • Prat J, Gallardo A, Cuatrecasas M, Catasús L. Endometrial carcinoma: pathology and genetics. Pathology 2007; 39:72 - 87
  • Holliday R. The inheritance of epigenetic defects. Science 1987; 238:163 - 170
  • Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 1999; 27:2291 - 2298
  • Turek-Plewa J, Jagodzinski PP. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett 2005; 10:631 - 647
  • Brenner C, Fuks F. DNA methyltransferases: facts, clues, mysteries. Curr Top Microbiol Immunol 2006; 301:45 - 66
  • Cross SH, Bird AP. CpG islands and genes. Curr Opin Genet Dev 1995; 5:309 - 314
  • Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349:2042 - 2054
  • Bird AP. Gene number, noise reduction and biological complexity. Trends Genet 1995; 11:94 - 100
  • Robertson KD. DNA methylation and human disease. Nat Rev Genet 2005; 6:597 - 610
  • Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001; 293:1089 - 1093
  • Gopalakrishnan S, Van Emburgh BO, Robertson KD. DNA methylation in development and human disease. Mutat Res 2008; 647:30 - 38
  • Heard E, Clerc P, Avner P. X-chromosome inactivation in mammals. Annu Rev Genet 1997; 31:571 - 610
  • Ideraabdullah FY, Vigneau S, Bartolomei MS. Genomic imprinting mechanisms in mammals. Mutat Res 2008; 647:77 - 85
  • Esteller M. Epigenetics in cancer. N Engl J Med 2008; 358:1148 - 1159
  • Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg 2001; 234:10 - 20
  • Wilson AG. Epigenetic regulation of gene expressio in the inflammatory response and relevance to common disease. J Periodontol 2008; 79:1514 - 1519
  • Liu L, van Groen T, Kadish I, Tollefsbol TO. DNA methylation impacts on learning and memory in aging. Neurobiol Aging 2009; 30:549 - 560
  • Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983; 301:89 - 92
  • Kisseljova NP, Kisseljova FL. DNA demethylation and carcinogenesis. Biochemistry 2005; 70:743 - 752
  • Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophs Acta 2007; 1775:138 - 162
  • Widschwendter M, Jones PA. DNA methylation and breast carcinogenesis. Oncogene 2002; 21:5462 - 5482
  • Nieminen TT, Gylling A, Abdel-Rahman WM, Nuorva K, Aarnio M, Renkonen-Sinisalo L, et al. Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia. Clin Cancer Res 2009; 15:5772 - 5783
  • Wheeler JMD. Epigenetics, mismatch repair genes and colorectal cancer. Ann R Coll Surg Engl 2005; 87:15 - 20
  • Caduff RF, Johnston CM, Svoboda-Newman SM, Poy EL, Merajver SD, Frank TS. Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma. Am J Pathol 1996; 148:1671 - 1678
  • Duggan BD, Felix JC, Muderspach LI, Tourgeman D, Zheng J, Shibata D. Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 1994; 86:1216 - 1221
  • Gurin CC, Federici MG, Kang L, Boyd J. Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res 1999; 59:462 - 466
  • Helland A, Børresen-Dale AL, Peltomäki P, Hektoen M, Kristensen GB, Nesland JM, et al. Microsatellite instability in cervical and endometrial carcinomas. Int J Cancer 1997; 70:499 - 501
  • Kobayashi K, Sagae S, Kudo R, Saito H, Koi S, Nakamura Y. Microsatellite instability in endometrial carcinomas: frequent replication errors in tumors of early onset and/or of poorly differentiated type. Genes Chromosomes Cancer 1995; 14:128 - 132
  • Muresu R, Sini MC, Cossu A, Tore S, Baldinu P, Manca A, et al. Chromosomal abnormalities and microsatellite instability in sporadic endometrial cancer. Eur J Cancer 2002; 38:1802 - 1809
  • Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 1998; 17:2413 - 2417
  • Katabuchi H, van Rees B, Lambers AR, Ronnett BM, Blazes MS, Leach FS, et al. Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res 1995; 155:5556 - 5560
  • Kobayashi K, Matsushima M, Koi S, Saito H, Sagae S, Kudo R, et al. Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in sporadic endometrial carcinomas with microsatellite instability. Jpn J Cancer Res 1996; 87:141 - 145
  • Lim PC, Tester D, Cliby W, Ziesmer SC, Roche PC, Hartmann L, et al. Absence of mutations in DNA mismatch repair genes in sporadic endometrial tumors with microsatellite instability. Clin Cancer Res 1996; 2:1907 - 1911
  • Staebler A, Lax SF, Ellenson LH. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability. Hum Pathol 2000; 31:354 - 358
  • Stefansson I, Akslen LA, MacDonald N, Ryan A, Das S, Jacobs IJ, et al. Loss of hMSH2 and hMSH6 expression is frequent in sporadic endometrial carcinomas with microsatellite instability: a population-based study. Clin Cancer Res 2002; 8:138 - 143
  • Baldinu P, Cossu A, Manca A, Satta MP, Pisano M, Casula M, et al. Microsatellite instability and mutation analysis of candidate genes in unselected sardinian patients with endometrial carcinoma. Cancer 2002; 94:3157 - 3168
  • Kondo E, Furukawa T, Yoshinaga K, Kijima H, Semba S, Yatsuoka T, et al. Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability. Int J Cancer 2000; 17:535 - 541
  • Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997; 57:808 - 811
  • Cunningham JM, Christensen ERTD, Kim CY, Roche PC, Burgart LJ, Thibodeau SN. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998; 58:3455 - 3460
  • Veigl ML, Kasturi L, Olechnowicz J, Ma A, Lutterbaugh JD, Periyasamy S, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc natl Acad Sci USA 1998; 95:8698 - 8702
  • Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, et al. Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 1999; 59:1090 - 1095
  • Simpkins SB, Bocker T, Swisher EM, Mutch DG, Gersell DJ, Kovatich AJ, et al. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet 1999; 8:661 - 666
  • Salvesen HB, MacDonald N, ryan A, Iversen OE, Jocobs IJ, akslen LA, et al. Methylation of hMLH1 in a population-based series of endometrial carcinomas. Clin Cancer Res 2000; 6:3607 - 3613
  • Zighelboim I, Goodfellow PJ, Gao F, Gibb RK, Powell MA, Rader JS, et al. Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol 2007; 25:2042 - 2048
  • Herman JG, Uma A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998; 95:6870 - 6875
  • Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB, et al. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol 1999; 155:1767 - 1772
  • Horowitz N, Pinto K, Mutch DG, Herzog TJ, Rader JS, Gibb R, et al. Microsatellite instability, MLH1 promoter methylation, and loss of mismatch repair in endometrial cancer and concomitant atypical hyperplasia. Gynecol Oncol 2002; 86:62 - 68
  • Kanaya T, Kyo S, Sakaguchi J, Maida Y, Nakamura M, Takakura M, et al. Association of mismatch repair deficiency with PTEN frameshift mutations in endometrial cancers and the precursors in a Japanese population. Am J Clin Pathol 2005; 124:89 - 96
  • Banno K, Yanokura M, Susumu N, Kawaguchi M, Hirao N, Hirasawa A, et al. Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. Oncol Rep 2006; 16:1189 - 1196
  • Guida M, Sanguedolce F, Bufo P, Di Spiezio Sardo A, Bifulco G, Nappi C, et al. Aberrant DNA hypermethylation of hMLH-1 and CDKN2A/p16 genes in benign, premalignant and malignant endometrial lesions. Eur J Gynaecol Oncol 2009; 30:267 - 270
  • Piva R, Kumar VL, Hanau S, Rimondi AP, Pansini S, Mollica G, et al. Abnormal methylation of estrogen receptor gene and reduced estrogen receptor RNA levels in human endometrial carcinomas. J Steroid Biochem 1989; 32:1 - 4
  • Sasaki M, Kotcherguina L, Dharia A, Fujimoto S, Dahiya R. Cytosine-phosphoguanine methylation of estrogen receptors in endometrial cancer. Cancer Res 2001; 61:3262 - 3266
  • Hori M, Iwasaki M, Shimazaki J, Inagawa S, Itabashi M. Assessment of hypermethylated DNA in two promoter regions of the estrogen receptor alpha gene in human endometrial diseases. Gynecol Oncol 2000; 76:89 - 96
  • Navari JR, Roland PY, Keh P, Salvesen HB, Akslen LA, Iversen OE, et al. Loss of estrogen receptor (ER) expression in endometrial tumors is not associated with de novo methylation of the 5′ end of the ER gene. Clin Cancer Res 2000; 6:4026 - 4032
  • Shiozawa T, Itoh K, Horiuchi A, Konishi I, Fujii S, Nikaido T. Downregulation of estrogen receptor by the methylation of the estrogen receptor gene in endometrial carcinoma. Anticancer Res 2002; 22:139 - 143
  • Maeda K, Tsuda H, Hashiguchi Y, Yamamoto K, Inoue T, Ishiko O, et al. Relationship between p53 pathway and estrogen receptor status in endometrioid-type endometrial cancer. Hum Pathol 2002; 33:386 - 391
  • Sasaki M, Kaneuchi M, Fujimoto S, Tanaka Y, Dahiya R. Hypermethylation can selectively silence multiple promoters of steroid receptors in cancers. Mol Cell Endocrinol 2003; 202:201 - 207
  • Kumar NS, Richer J, Owen G, Litman E, Horwitz KB, Leslie KK. Selective downregulation of progesterone receptor isoform B in poorly differentiated human endometrial cancer cells: implications for unopposed estrogen action. Cancer Res 1998; 58:1860 - 1865
  • Sasaki M, Dharia A, Oh BR, Tanaka Y, Fujimoto S, Dahiya R. Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. Cancer Res 2001; 61:97 - 102
  • Dai D, Wolf DM, Litman ES, White MJ, Leslie KK. Progesterone inhibits human endometrial cancer cell growth and invasiveness: downregulation of cellular adhesion molecules through progesterone B receptors. Cancer Res 2002; 62:881 - 886
  • Xiong Y, Dowdy SC, Gonzalez Bosquet J, Zhao Y, Eberhardt NL, Podratz KC, et al. Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines. Gynecol Oncol 2005; 99:135 - 141
  • Ren Y, Liu X, Ma D, Feng Y, Zhong N. Downregulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells. Cancer Genet Cytogenet 2007; 175:107 - 116
  • Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 1996; 13:114 - 116
  • Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, et al. Germ-line mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 1997; 16:333 - 334
  • Waite KA, Eng C. Protean PTEN: Form and Function. Am J Hum Genet 2002; 70:829 - 844
  • Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997; 27:3935 - 3940
  • Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924 - 930
  • Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 2004; 64:3014 - 3021
  • Macdonald ND, Salvesen HB, Ryan A, Malatos S, Stefansson I, Iversen OE, et al. Molecular differences between RER+ and RER− sporadic endometrial carcinomas in a large population-based series. Int J Gynecol Cancer 2004; 14:957 - 965
  • Salvesen HB, Stefansson I, Kretzschmar EI, Gruber P, MacDonald ND, Ryan A, et al. Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression. Int J Oncol 2004; 25
  • Salvesen HB, MacDonald N, Ryan A, Jacobs IJ, Lynch ED, Akslen LA, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer 2001; 91:22 - 26
  • Zysman MA, Chapman WB, Bapat B. Considerations when analyzing the methylation status of PTEN tumor suppressor gene. Am J Pathol 2002; 160:795 - 800
  • Liggett WH Jr, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol 1998; 16:1197 - 1206
  • Wong YF, Chung TK, Cheung TH, Nobori T, Yu AL, Yu J, et al. Methylation of p16INK4A in primary gynecologic malignancy. Cancer Lett 1999; 136:231 - 235
  • Ignatov A, Bischoff J, Schwarzenau C, Krebs T, Kuester D, Herrmann K, et al. p16 alterations increase the metastatic potential of endometrial carcinoma. Gynecol Oncol 2008; 111:365 - 371
  • Furlan D, Carnevali I, Marcomini B, Cerutti R, Dainese E, Capella C, et al. The high frequency of de novo promoter methylation in synchronous primary endometrial and ovarian carcinomas. Clin Cancer Res 2006; 12:3329 - 3336
  • Yang HJ, Liu VW, Wang Y, Tsang PC, Ngan HY. Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. BMC Cancer 2006; 23:212
  • Nakashima R, Fujita M, Enomoto T, Haba T, Yoshino K, Wada H, et al. Alteration of p16 and p15 genes in human uterine tumours. Br J Cancer 1999; 80:458 - 467
  • Salesen HB, Das S, Akslen LA. Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res 2000; 153 - 159
  • Semczuk A, Boltze C, Marzec B, Szczygielska A, Roessner A, Schneider-Stock R. p16INK4A alterations are accompanied by aberrant protein immunostaining in endometrial carcinomas. J Cancer Res Clin Oncol 2003; 129:589 - 596
  • Agathanggelou A, Cooper WN, Latif F. Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res 2005; 65:3497 - 3508
  • Donninger H, Vos MD, Clark GJ. The RASSF1A tumor suppressor. J Cell Sci 2007; 120:3163 - 3172
  • Arafa M, Kridelka F, Mathias V, Vanbellinghen JF, Renard I, Foidart JM, et al. High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarcinoma. Histopathology 2008; 53:525 - 532
  • Pallarés J, Velasco A, Eritja N, Santacana M, Dolcet X, Cuatrecasas M, et al. Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma. Mod Pathol 2008; 21:691 - 699
  • Liao X, Siu MK, Chan KY, Wong ES, Ngan HY, Chan QK, et al. Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis. Int J Cancer 2008; 123:296 - 302
  • Pijnenborg JM, Dam-de Veen GC, Kisters N, Delvoux B, van Engeland M, Herman JG, et al. RASSF1A methylation and K-ras and B-raf mutations and recurrent endometrial cancer. Ann Oncol 2007; 18:491 - 497
  • Jo H, Kim JW, Kang GH, Park NH, Song YS, Kang SB, et al. Association of promoter hypermethylation of the RASSF1A gene with prognostic parameters in endometrial cancer. Oncol Res 2006; 16:205 - 209
  • Kang S, Lee JM, Jeon ES, Lee S, Kim H, Kim HS, et al. RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma. Int J Cancer 2006; 119:1316 - 1321
  • Joensuu EI, Abdel-Rahman WM, Ollikainen M, Ruosaari S, Knuutila S, Peltomäki P. Epigenetic signatures of familial cancer are characteristic of tumor type and family category. Cancer Res 2008; 68:4597 - 4605
  • Yu MY, Tong JH, Chan PK, Lee TL, Chan MW, Chan AW, et al. Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers. Int J Cancer 2003; 105:204 - 209
  • Jones MH, Nakamura Y, Koi S, Fujimoto L, Hasumi K, Kato K. Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: Frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q and 17p. Genes Chromosomes Cancer 1994; 9:119 - 123
  • Kang S, Kim JW, Kang GH, Lee S, Park NH, Song YS, et al. Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma. Int J Cancer 2006; 118:2168 - 2171
  • Fodde R. The APC gene in colorectal cancer. Eur J Cancer 2002; 38:867 - 871
  • Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays 2000; 22:961 - 965
  • Schlosshauer PW, Pirog EC, Levine RL, Ellenson LH. Mutational analysis of the CTNNB1 and APC genes in uterine endometrioid carcinoma. Mod Pathol 2000; 13:1066 - 1071
  • Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta-catenin gene in endometrial carcinomas. Jpn J Cancer Res 1999; 90:55 - 59
  • Moreno-Bueno G, Hardisson D, Sánchez C, Sarrió D, Cassia R, García-Rostán G, et al. Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 2002; 21:7981 - 7990
  • Pijnenborg JM, Kisters N, van Engeland M, Dunselman GA, de Haan J, de Goeij AF, et al. APC, beta-catenin and E-cadherin and the development of recurrent endometrial carcinoma. Int J Gynecol Cancer 2004; 14:947 - 956
  • Zysman M, Saka A, Millar A, Knight J, Chapman W, Bapat B. Methylation of adenomatous polyposis coli in endometrial cancer occurs more frequently in tumors with microsatellite instability phenotype. Cancer Res 2002; 62:3663 - 3666
  • Suehiro Y, Okada T, Okada T, Anno K, Okayama N, Ueno K, et al. Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation. Clin Cancer Res 2008; 14:3354 - 3361
  • Ilyas M, Tomlinson IPM. The interatcions of APC, E-cadherin and β-catenin in tumor development and progression. J Pathol 1997; 182:128 - 137
  • Moreno-Bueno G, Hardisson D, Sarrió D, Sánchez C, Cassia R, Prat J, et al. Abnormalities of E- and P-cadherin and catenin (beta-, gamma-catenin and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol 2003; 199:471 - 478
  • Saito T, Nishimura M, Yamasaki H, Kudo R. Hypermethylation in promoter region of E-cadherin gene is associated with tumor dedifferention and myometrial invasion in endometrial carcinoma. Cancer 2003; 97:1002 - 1009
  • Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999; 59:793 - 797
  • Li R, Saito T, Tanaka R, Satohisa S, Adachi K, Horie M, et al. Hypermethylation in promoter region of retinoic acid receptor-beta gene and immunohistochemical findings on retinoic acid receptors in carcinogenesis of endometrium. Cancer Lett 2005; 219:33 - 40
  • Mhawech P, Benz A, Cerato C, Greloz V, Assaly M, Desmond JC, et al. Downregulation of 14-3-3sigma in ovary, prostate and endometrial carcinomas is associated with CpG island methylation. Mod Pathol 2005; 18:340 - 348
  • Dowdy SC, Gostout BS, Shridhar V, Wu X, Smith DI, Podratz KC, et al. Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines. Gynecol Oncol 2005; 99:126 - 134
  • Chan QK, Khoo US, Chan KY, Ngan HY, Li SS, Chiu PM, et al. Promoter methylation and differential expression of pi-class glutathione S-transferase in endometrial carcinoma. J Mol Diagn 2005; 7:8 - 16
  • Yamaguchi S, Asanoma K, Takao T, Kato K, Wake N. Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor. Int J Cancer 2009; 124:2577 - 2588
  • Yoshida H, Broaddus R, Cheng W, Xie S, Naora H. Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial-mesenchymal transition. Cancer Res 2006; 66:889 - 897
  • Whitcomb BP, Mutch DG, Herzog TJ, Rader JS, Gibb RK, Goodfellow PJ. Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma. Clin Cancer Res 2003; 9:2277 - 2287
  • Yoshizaki T, Enomoto T, Fujita M, Ueda Y, Miyatake T, Fujiwara K, et al. Frequent inactivation of RUNX3 in endometrial carcinoma. Gynecol Oncol 2008; 110:439 - 444
  • Tse KY, Liu VW, Chan DW, Chiu PM, Tam KF, Chan KK, et al. Epigenetic alteration of the metallothionein 1E gene in human endometrial carcinomas. Tumour Biol 2009; 30:93 - 99
  • Risinger JI, Maxwell GL, Berchuck A, Barrett JC. Promoter hypermethylation as an epigenetic component in Type I and Type II endometrial cancers. Ann N Y Acad Sci 2003; 983:208 - 212
  • Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA. Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod Pathol 2006; 19:1091 - 1100
  • Xiong Y, Dowdy SC, Xue A, Shujuan J, Eberhardt NL, Podratz KC, et al. Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers. Gynecol Oncol 2005; 96:601 - 609
  • Herceg Z. Epigenetics and cancer: towards an evaluation of the impact of enironmental and dietary factors. Mutagenesis 2007; 22:91 - 103
  • Mason JB. Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J Nutr 2003; 133:941 - 947
  • Choi SW, Mason JB. Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 2002; 132:2413 - 2418
  • Kim YI. Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. J Nutr 2005; 135:2703 - 2709
  • Mason JB, Choi SW, Liu Z. Other one-carbon micro-nutrients and age modulate the effects of folate on colorectal carcinogenesis. Nutr Rev 2008; 66:15 - 17
  • Thompson J. Vitamins and minerals 4: overview of folate and the B vitamins. Community Pract 2006; 79:197 - 198
  • Pufulete M, Emery PW, Sanders TA. Folate, DNA methylation and colo-rectal cancer. Proc Nutr Soc 2003; 62:437 - 445
  • Kim YI, Pogribny IP, Basnakian AG, Miller JW, Selhub J, James SJ, et al. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J Clin Nutr 1997; 65:46 - 52
  • Pogribny IP, James SJ. De novo methylation of the p16INK4A gene in early preneoplastic liver and tumors induced by folate/methyl deficiency in rats. Cancer Lett 2002; 187:69 - 75
  • de Vogel S, Bongaerts BW, Wouters KA, Kester AD, Schouten LJ, de Goeij AF, et al. Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer. Carcinogenesis 2008; 29:1765 - 1773
  • Kraunz KS, Hsiung D, McClean MD, Liu M, Osanyingbemi JO, Nelson HH, et al. Dietary folate is associated with p16INK4A methylation in head and neck squamous cell carcinoma. Int J Cancer 2006; 119:1553 - 1557
  • Slattery ML, Curtin K, Sweeney C, Levin TR, Potter J, Wolff RK, et al. Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer 2006; 120:656 - 663
  • van Engeland M, Weijenberg MP, Roemen GM, Brink M, de Bruïne AP, Goldbohm RA, et al. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 2003; 63:3133 - 3137
  • Zhu K, Davidson NE, Hunter S, Yang X, Payne-Wilks K, Roland CL, et al. Methyl-group dietary intake and risk of breast cancer among African-American women: a case-control study by methylation status of the estrogen receptor alpha genes. Cancer Causes Control 2003; 14:827 - 836
  • Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 1999; 18:3166 - 3172
  • Wietrzyk J, Boratynski J, Grynkiewicz G, Ryczynski A, Radzikowski C, Opolski A. Antiangiogenic and antitumour effects in vivo of genistein applied alone or combined with cyclophosphamide. Anticancer Res 2001; 21:3893 - 3896
  • Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncol 2002; 3:364 - 373
  • Price KR, Fenwick GR. Naturally occurring oestrogens in foods-a review. Food Addit Contam 1985; 2:73 - 106
  • Day JK, Bauer AM, DesBordes C, Zhuang Y, Kim BE, Newton LG, et al. Genistein alters methylation patterns in mice. J Nutr 2002; 132:2419 - 2423
  • Fang MZ, Chen D, Sun Y, Jin Z, Christman JK, Yang CS. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta and MGMT genes by genistein and ther isoflavones from soy. Clin Cancer Res 2005; 11:7034 - 7041
  • Cui Y, Lu C, Liu L, Sun D, Yao N, Tan S, et al. Reactivation of methylation-silenced tumor suppressor gene p16INK4a by nordihydroguaiaretic acid and its implication in G1 cell cycle arrest. Life Sci 2008; 82:247 - 255
  • King-Batoon A, Leszczynska JM, Klein CB. Modulation of gene methylation by genistein or lycopene in breast cancer cells. Environ Mol Mutagen 2008; 49:36 - 45
  • Majid S, Dar AA, Ahmad AE, Hirata H, Kawakami K, Shahryari V, et al. BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis 2009; 30:662 - 670
  • Qin W, Zhu W, Shi H, Hewett JE, Ruhlen RL, MacDonald RS, et al. Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women. Nutr Cancer 2009; 61:238 - 244
  • Coyle YM, Xie XJ, Lewis CM, Bu D, Milchgrub S, Euhus DM. Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue. Cancer Epidemiol Biomarkers Prev 2007; 16:192 - 196
  • Vessey MP, Painter R. Endometrial and ovarian cancer and oral contraceptives-findings in a large cohort study. Br J Cancer 1995; 71:1340 - 1342
  • Tao MH, Xu WH, Zheng W, Zhang ZF, Gao YT, Ruan ZX, et al. Oral contraceptive and IUD use and endometrial cancer: a population-based case-control study in Shanghai, China. Int J Cancer 2006; 119:2142 - 2147
  • Maxwell GL, Schildkraut JM, Calingaert B, Risinger JI, Dainty L, Marchbanks PA, et al. Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk. Gynecol Oncol 2006; 103:535 - 540
  • Yamagata Y, Asada H, Tamura I, Lee L, Maekawa R, Taniguchi K, et al. DNA methyltransferase expression in the human endometrium: downregulation by progesterone and estrogen. Hum Reprod 2009; 24:1126 - 1132
  • Foley DL, Craig JM, Morley R, Olsson CJ, Dwyer T, Smith K, et al. Prospects for epigenetic epidemiology. Am J Epidemiol 2009; 169:389 - 400

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.