Epigenetic regulation of telomeres in human cancer

Vera, Elsa; Canela, Andrés; Fraga, Mario F.; Esteller, Manel; Blasco, Marı́a A.

doi:10.1038/onc.2008.289

Cited by 114 publications

(101 citation statements)

References 30 publications

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“…This is evidenced by the low methylation level of pericentromeric Sat2 DNA and Alu repeats, two markers of genome-wide demethylation in tumors (Weisenberger et al, 2005;Cadieux et al, 2006;Ehrlich, 2006), in ALT tumor cell lines. It is worth noting that when this article was in preparation, a study on epigenetic regulation of human telomeres reported no correlation between the methylation level of subtelomeric DNA and the pericentromeric repeat NBL2 DNA (Vera et al, 2008). We believe that the discrepancy between this study and the present one may be related to the fact that NBL2-repeated sequences are known to undergo opposite cancer-linked epigenetic changes, displaying either hypomethylation or, more frequently, predominant hypermethylation in tumors (Ehrlich, 2006).…”

Section: Discussioncontrasting

confidence: 81%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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Most human tumor cells acquire immortality by activating the expression of telomerase, a ribonucleoprotein that maintains stable telomere lengths at chromosome ends throughout cell divisions. Other tumors use an alternative mechanism of telomere lengthening (ALT), characterized by high frequencies of telomeric sister chromatid exchanges (T-SCEs). Mechanisms of ALT activation are still poorly understood, but recent studies suggest that DNA hypomethylation of chromosome ends might contribute to the process by facilitating T-SCEs. Here, we show that ALT/T-SCE high tumor cells display low DNAmethylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCE high SV40-immortalized fibroblasts. Moreover, T-SCE rates were efficiently reduced by ectopic expression of active telomerase in ALT tumor cells, even though subtelomeric sequences remained hypomethylated. We also show that hypomethylation of subtelomeric sequences in ALT tumor cells is correlated with genome-wide hypomethylation of Alu repeats and pericentromeric Sat2 DNA sequences. Overall, this study suggests that, although subtelomeric DNA hypomethylation is often coincident with the ALT process in human tumor cells, it is not required for T-SCE.

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Section: Discussioncontrasting

confidence: 81%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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“…32 In these studies, the methylation frequency was evaluated by BGS at two subtelomeric sites, and DNA methylation of subtelomeric D4Z4 repeats on chromosome 4q showed a significant negative correlation with telomere length (p < 0.01), while the other site, an independent subtelomeric repeat, SRH, located on chromosomes 1, 9, 15, 16 and X, showed a marginally significant negative correlation (p ¼ 0.07). 32 In our study, correlations between telomere length and methylation ratio were found in certain regions of subtelomeres. Methylation at 7q gradually decreased with telomere lengthening of HCCs, and a similar relationship was found at 18p in both HCCs and non-HCCs, indicating that hypomethylation in these regions might be related to long telomeres.…”

Section: Discussionmentioning

confidence: 99%

Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

Choi

et al. 2010

Intl Journal of Cancer

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Subtelomeric chromatin modifications are important regulators of telomere length. We examined the subtelomeric DNA methylation status of 7q, 8q, 17q, 18p, 21q and XpYp in 32 pairs of hepatocellular carcinomas (HCCs) and their adjacent nonHCCs via methylation-specific PCR (quantified as methylation ratio). In addition, 10q was subjected to bisulfite-genomicsequencing. Telomere length was determined by Southern hybridization. In all cases, the relationship between methylation ratio and telomere length was determined. High levels of methylation ratio were found on chromosomes 7q, 18p and XpYp, whereas 8q 17q and 21q were less methylated in both HCCs and non-HCCs. Compared to non-HCCs, HCCs exhibited a higher methylation ratio on 18p and 21q, and a wider distribution of methylation ratio on 7q, 21q and 10q (p < 0.05). The methylation ratio of 18p and of 21q was negatively and positively correlated with telomere length of HCCs, respectively (p < 0.05). We evaluated changes in methylation pattern between non-HCCs and HCCs. Out of 185 sites, hypermethylation changes from non-HCC to HCC were found at 47 sites and hypomethylation changes at 31 sites. Changes in methylation pattern were observed at three to four sites among six chromosomal sites in 15 patients (47%). There was a tendency toward hypomethylation changes at 7q (p 5 0.013) and hypermethylation changes at 21q (p 5 0.057) when telomere lengthened from non-HCCs to HCCs. In summary, subtelomeric methylation patterns dynamically changed during hepatocarcinogenesis. Subtelomeric methylation at certain regions was related to telomere lengthening or shortening, suggesting an association between subtelomeric chromatin structure and telomere length regulation in human hepatocarcinogenesis.

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“…Therefore, the researchers focused on the putative effects of the epigenetic changes in cancer for development of early diagnosis methods and new therapeutic approaches (25,26). This new perspective was proven by Vera et al They found an association between DNA methylation of global/ subtelomeric region and telomere-SCE frequency (27).…”

Section: Figure 1 Sce Distribution Of Measurements According To Groupsmentioning

confidence: 96%

Increased Sister Chromatid Exchanges in Patients with Gastrointestinal Cancers and in their First-Degree Relatives

Turgut

Yaşar²,

Yaykaşlı

et al. 2014

Electron J Gen Med

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Gastrointestinal Cancers (GICs) European Journal of General MedicineOriginal Article Eur J Gen Med 2014; 11(2): 94-98 DOI : 10.15197/sabad.1.11. 46 Eur J Gen Med 2014;11(2): 94-98 Increased sister chromatid exchange in gastrointestinal cancers 95 MATERIALS AND METHODSThis study was conducted at Düzce University Medical Faculty, Department of Medical Genetics, Düzce, Turkey. The study groups consisted of 15 GIC patients (2 esophagus, 6 stomach, 6 colon and 1 rectum), 13 relatives and 15 healthy subjects. Approved ethical certificate was obtained from local ethics committee, and written informed consents of the studied cases were obtained. Age, gender, smoking and alcohol consumption status and tumor markers (alpha-fetoprotein, AFP, carcinoembryonic antigen-CEA, carcinogenic antigen (CA) 125, CA19-9, CA15-3) were recorded. Two milliliters of venous blood was drawn using Na-heparinized syringes from each case. Replication Index was calculated by following formula.RPI: R1 + (R2x2) + (R3x3) / R1 + R2 + R3Mitotic index (MTI) was calculated by following formula. MTI: metaphase/metaphase+lymphocyte count Statistical analysisThe frequency of SCE per metaphase in groups was compared by Kruskal Wallis. Mann-Whitney U test was also used. Relationships between parameters were evaluated with the Spearman's correlation analysis. Qualitative data were compared using Chi-square test. Results with 95% confidence interval and p<0.05 were considered significant.

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Epigenetic regulation of telomeres in human cancer

Cited by 114 publications

References 30 publications

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Frequent changes in subtelomeric DNA methylation patterns and its relevance to telomere regulation during human hepatocarcinogenesis

Increased Sister Chromatid Exchanges in Patients with Gastrointestinal Cancers and in their First-Degree Relatives

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