DNA hypomethylation is prevalent even in low-grade breast cancers

Jackson, Kesmic; Yu, Mimi C.; Arakawa, Kazuko; Fiala, Emerich S.; Youn, Byungwoo; Fiegl, Heidi; Müller‐Holzner, Elisabeth; Widschwendter, Martin; Ehrlich, Melanie

doi:10.4161/cbt.3.12.1222

Cited by 109 publications

(87 citation statements)

References 34 publications

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“…Individuals undergo extensive changes in DNA methylation patterns during their lifespan, in accordance with the changes in their tissue-specific gene expression patterns related to aging and other physiologic states. 37 It is well established that alterations in DNA methylation represent early events in carcinogenesis, [1][2][3][4][5][6][7][8]24 characterized by genome-wide hypomethylation, especially at repetitive elements throughout the genome, such as LINE-1, and gene-specific promoter hypermethylation, which affects expression of tumor suppressor genes. 1-6, 25,35, 38 Histologically normal tissues are known to maintain a high percent methylation of LINE-1 (ranging from approximately 7585%-).…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22][23][24] Additionally, compared to histologically normal or normal-appearing tissues (adjacent to breast tumors), tumor tissues consistently have lower levels of DNA methylation (i.e., increased hypomethylation throughout the genome), even early in breast carcinogenesis. 4,5,25 Furthermore, there are reports of significant associations between LINE-1 methylation and breast tumor clinicopathological features, 3 as well as breast cancer prognosis. 3,4 Current evidence regarding associations between variants in the folate-mediated one-carbon metabolism pathway and DNA methylation suggests that this relationship is a complex one, with evidence supporting a role of this pathway in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Genome-wide DNA hypomethylation and gene promoter hypermethylation are early events in the carcinogenic process [1][2][3][4][5] and have been linked to chromosomal instability, gene reactivation, activation of proto-oncogenes, and higher frequencies of mutation and recombination events, [6][7][8][9][10] all of which are characteristics of cancer genomes, including cancers of the breast. [11][12][13] Long interspersed nucleotide element-1 (LINE-1) is a major constituent of repetitive transposable elements in the human genome.…”

Section: Introductionmentioning

confidence: 99%

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Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Llanos

Marian²,

Brasky

et al. 2015

Epigenetics

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Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Llanos

Marian²,

Brasky

et al. 2015

Epigenetics

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“…Hypomethylation of Sata Sat2 and LINE-1 elements has also been detected in benign breast and colon tumors (Chalitchagorn et al, 2004;Jackson et al, 2004;Widschwendter et al, 2004). It should be noted that a base composition analysis of DNA extracted from colonic tissues indicates significant hypomethylation of colonic adenomas (Feinberg et al, 1988), and that a relationship has been suggested between the extent of demethylation in hyperplastic polyps and the proliferative rate of adenomas (Bariol et al, 2003).…”

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confidence: 99%

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Ballestar

Fraga

et al. 2006

Oncogene

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In human post-natal somatic cells, low global levels of DNA methylation have been associated with the hypomethylation of several repetitive elements, a feature that has been proposed to be a surrogate epigenetic marker. These data, mainly derived from the analysis of cancer cells, suggest a potential association between loss of cellgrowth control and altered differentiation with hypomethylation of repetitive sequences. Partial hydatidiform moles (PHMs) can be used as an alternative model for investigating this association in a non-tumorigenic context. This gestational disease is characterized by abnormal overgrowth and differentiation of the placenta and spontaneous abortion. Here, we comprehensively analyse the DNA methylation of these trophoblastic tissues in both PHM and normal placenta at global and sequencespecific levels. Analysis of the global 5-methylcytosine content and immunohistochemistry indicate that PHM and normal placenta have identical global levels of DNA methylation. In contrast, bisulfite genomic sequencing shows that, whereas Alu, NBL2 and satellite 2 repetitive elements are equally methylated, LINE-1 sequences are hypermethylated in PHM tissues (B2-fold relative to normal placenta). Interestingly, altered demethylation is also found in triploid diandric embryos that originate from dispermic fertilization of an oocyte, a common event responsible for most PHMs. In conclusion, alterations of DNA methylation do not seem to be randomly distributed in PHM, as several repeated elements remain unaltered, whereas LINE-1 sequences are hypermethylated. In addition, our findings suggest that the hypomethylation of repetitive elements in cancer is directly linked to the neoplasic process and not a simple consequence of loss of growth control observed in most of the cancer cells.

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“…[12][13][14] Altered methylation is thought to be an early event in breast cancer and the number of genes affected increases with progression. [15][16][17] Epigenetic changes like methylation may also affect key players in the PI3K/ AKT pathway. [18][19][20] Although genome-wide copy number alterations have been previously studied, 21 little is known so far about genome-wide methylation changes in HER2+ breast cancer.…”

Section: Introductionmentioning

confidence: 99%