Coordinate hypermethylation at specific genes in prostate carcinoma precedes LINE-1 hypomethylation

Florl, Andrea R.; Steinhoff, Christine; Müller, Mirko; Seifert, H-H; Hader, Christiane; Engers, Rainer; Ackermann, R.; Schulz, Wolfgang A.

doi:10.1038/sj.bjc.6602030

Cited by 157 publications

(150 citation statements)

References 26 publications

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“…24 Moreover, it has been suggested that a high de-repression, via hypomethylation, of LINE-1 promoter could induce a general dysregulation that involves chromosomal instability, reactivation of repeated sequences, and oncogenes. 24,22 Our results are consistent with these suggestions, as the association between LINE-1 hypomethylation and mortality from prostate cancer was limited to men with an aggressive tumor (Gleason score 8C). On the other hand, there was no association between LINE-1 methylation and Gleason score.…”

Section: Discussionsupporting

confidence: 81%

“…On the other hand, there was no association between LINE-1 methylation and Gleason score. Although this latter finding is not completely inconsistent with previous studies (a clear association between LINE-1 hypomethylation and Gleason score has been found only in one out of 3 previous studies 22,23,26 ), if global methylation was a late event in prostate cancerogenesis, we would have expected higher hypomethylation among patients with a Gleason score of at least 8. It could be speculated that global methylation is more related to the metastatic potential of aggressive prostate cancers than to the Gleason score, and it is of interest that previous studies strongly indicate a decreased global methylation in the prostate cancer tissue among prostate cancer patients with systemic metastases.…”

Section: Discussioncontrasting

confidence: 54%

“…We have recently conducted a systematic review of studies on prostatic tumor global hypomethylation and prostate cancer progression: 19 although studies were heterogeneous and mostly based on a limited sample size, global hypomethylation was reported to be associated with high Gleason score, advanced tumor stage, high pre-operative PSA, and presence of metastasis. [20][21][22][23][24][25][26] The genome-wide methylation level of the long interspersed nuclear element-1 (LINE-1) is considered as a good surrogate marker for global methylation, [27][28][29] as LINE-1 is widely interspersed and represents about 15% of human genome. 30,31 Thus, in the present study we have analyzed prostate tissue LINE-1 methylation status in a cohort of prostate cancer patients in association with Gleason score, gene-specific hypermethylation, and mortality from prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

et al. 2016

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Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982-1988 and 1993-1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95-2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (<75%) vs. high (>80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03-21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression.Abbreviations: NTAT, non-neoplastic tissue adjacent to tumor; LINE-1, long interspersed nuclear element-1; PIN, prostatic intraepithelial neoplasia; APC, adenomatous polyposis coli; GSTP1, glutathione S-transferase 1; TURP, transurethral resection of the prostate; HR, hazard ratio; CI, confidence interval; MAR, missing at random

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Section: Discussionsupporting

confidence: 81%

Section: Discussioncontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

et al. 2016

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“…DNA methylation (and heterochromatin in general) has been reported to suppress homologous recombination (Pàldi et al, 1995;Maloisel and Rossignol, 1998;Schnable et al, 1998;Fu et al, 2002;Yao et al, 2002;Yamada et al, 2004;Myers et al, 2005) as well as transposition (Yoder et al, 1997;Walsh et al, 1998;Hirochika et al, 2000;Robertson, 2001;Bird, 2002;Kato et al, 2003). Accordingly, reports of deletions caused by homologous recombination between LINE-1 elements are rare (Segal et al, 1999) except in cancers (Florl and Schulz, 2003) where LINE-1 elements are frequently hypomethylated (Santourlidis et al, 1999;Takai et al, 2000;Ehrlich, 2002;Carnell and Goodman, 2003;Florl et al, 2004;Roman-Gomez et al, 2005). LINE-1 transposition has also been reported to be elevated in cancers (Schulz, 2006).…”

Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 99%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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“…28 Esteller et al showed that 18% of sporadic colorectal carcinoma and adenoma harbour a methylated APC promoter, that in 95% of cases, methylation affects the wild-type allele and that neoplasia with methylation fail to express the APC transcript. 26 Studies in lung, prostate and breast cancer also demonstrated frequent APC methylation, [29][30][31] whereas there is no data concerning APC methylation frequencies in sarcoma. Our analysis of 20 myxoid/round-cell LPS samples revealed methylation in 45% of cases and showed that most methylated tumours displayed a lower APC transcript level than nonmethylated tumours.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

Sievers

Fritzsch

Lehnhardt

et al. 2006

Intl Journal of Cancer

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The adenomatous polyposis coli (APC) protein is a key component of the WNT signalling pathway wherein it acts as a scaffolding protein in controlling the level of the proto-oncoprotein b-catenin. Although APC has been shown to be genetically or epigenetically inactivated in a variety of carcinomas, little is known about its role in sarcoma. Liposarcomas (LPSs) are the second most common soft tissue sarcoma in adults. Despite different histology and malignancy, the myxoid and round-cell LPSs belong to one tumour entity characterized by a specific chromosomal translocation. We assessed the extent of genetic and epigenetic inactivation of the APC gene in myxoid/round-cell LPS. Sequencing of the mutation cluster region, the protein truncation test and a loss of heterozygosity (LOH) analysis did not reveal any genetic alterations of the APC gene in all of the liposarcoma samples. Methylation of the APC promoter was detected by methylation-specific PCR in 9 of 20 (45%) tumours. Analysis of APC expression by semiquantitative RT-PCR in a subset of the samples demonstrated that tumours with a methylated APC promoter showed a downregulation of the APC transcript. However, APC downregulation was not correlated with a stabilisation of the b-catenin protein.Thus, the epigenetic regulation of the APC gene might play an important role in the pathogenesis of myxoid/round-cell LPS. However, the impact of APC methylation on liposarcoma development is quite likely not mediated through WNT signalling. ' 2006 Wiley-Liss, Inc.Key words: adenomatous polyposis coli; methylation; liposarcoma Even though genetic hits leading to carcinogenesis have been well characterized, the role of epigenetic factors in tumour formation is just emerging. Epigenetics makes an impact on such different fields as chromosomal stability, silencing of retroelements and the setup and maintenance of a cell's expression status, thereby functioning as cellular memory. In the latter context, the promoter hypermethylation of tumour suppressor genes leading to their aberrant transcriptional silencing has been intensively studied. 1 It has also been shown that epigenetic phenomena such as DNA methylation and histone modification can be considered diagnostic or even prognostic markers. 2,3 The APC tumour suppressor protein exhibits diverse functions in the cell, whereby its role in the WNT signalling pathway is especially well described. It therein acts as a scaffolding protein in a multimeric protein complex, together with Axin and glycogen synthase kinase-3b (GSK-3b), which binds and phosphorylates the proto-oncoprotein b-catenin. Upon binding of a WNT protein to one of its receptors, the intracellular protein dishevelled inactivates GSK-3b. As a consequence, b-catenin can no longer be phosphorylated and hence marked for degradation. b-catenin then translocates into the nucleus, where it interacts with transcription factors of the TCF/LEF (T-cell factor/lymphoid enhancing factor) family. This interaction stimulates the transcription of WNT target genes like myc and...

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Coordinate hypermethylation at specific genes in prostate carcinoma precedes LINE-1 hypomethylation

Cited by 157 publications

References 26 publications

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

Repetitive sequence environment distinguishes housekeeping genes

Hypermethylation of the APC promoter but lack of APC mutations in myxoid/round‐cell liposarcoma

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