Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma

Greger, Valerie; Debus, Nils; Lohmann, Dietmar; Höpping, W; Passarge, Eberhard; Horsthemke, Bernhard

doi:10.1007/bf00211013

Cited by 161 publications

(102 citation statements)

References 15 publications

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“…DNA methylation that results in gene silencing during tumorigenesis has been observed in numerous genes, including Ecadherin, RB, p16, p15, MLH1, and PTEN [17][18][19][20]. In this study, we demonstrated that methylation of the ER gene occurred in nearly half of the breast cancer cases and is highly correlated with ER-negativity (P < 0.00001) and BRCA1 methylation (odds ratio 3.12, 95% confidence interval 1.10-9.68, P = 0.02).…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

Dignam

Nanda

et al. 2007

Breast Cancer Res Treat

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Estrogen receptor α (ER) and its ligand estrogen play vital roles in the development, progression and treatment of breast cancer. An increasing number of studies have also provided evidence linking disruption of the Fanconi anemia/BRCA cascade to breast cancer. Our objectives were to examine the methylation status and expression profiles of ER, correlate the findings with BRCA1 and FANCF methylation and map the critical CpGs for ER expression. We found that the CpG islands in the 5′ region of the ER gene are methylated in 59 of 120 (49.2%) primary breast cancers, including 45 of 59 ER-negative tumors (76.3%, P < 0.00001). In addition, we observed a strong correlation between ER promoter and BRCA1 promoter methylation (odds ratio 3.12, 95% confidence interval 1.10-9.68, P = 0.02). In contrast, FANCF methylation was rare in breast tumors: one of 120 (0.8%). ER methylation was associated with high tumor grade (60.4% methylated vs. 39.6% unmethylated in grade 3 tumors, P = 0.04) and tumor subtype (P = 0.03). Though small in number, all tumors of the medullary subtype were ER methylated. In contrast, the lobular subtype had the least methylation (23.1% methylated vs. 76.9% unmethylated). After treatment of MDA-MB-231 cells with 5-aza-cytidine (5-aza-dC) and trichostatin, which resulted in re-expression of ER mRNA, we localized dramatic demethylation effects to CpG islands in positions +68, +165, +192, +195, +337, +341 and +405 from transcription start site of the ER promoter. These data suggest that unlike FANCF, both ER and BRCA1 are specifically targeted for methylation in sporadic breast cancers, a phenomenon that should be explored for development of novel diagnostic and therapeutic approaches. HHS Public Access

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

Dignam

Nanda

et al. 2007

Breast Cancer Res Treat

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“…It contains CpG islands that are frequent sites of methylation (Ohtani-Fujita et al, 1993;Stirzaker et al, 1997). Hypermethylation in the RB1 promoter region has been reported in 13% of unilateral retinoblastomas (Greger et al, 1994;Sakai et al, 1991) and 27% of pituitary adenomas (Simpson et al, 2000), suggesting that promoter hypermethylation is an alternative mechanism for mutational loss of RB1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Hypermethylation has been considered one of the mechanisms of inactivation of the RB1 gene in the two-hit theory, because the majority of retinoblastomas with promoter hypermethylation showed LOH on the RB1 locus (Greger et al, 1994;Sakai et al, 1991). However, there is recent evidence that hypermethylation without LOH at this locus may be sufficient to cause loss of RB1 expression.…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

Nakamura

Yonekawa

Kleihues

et al. 2001

Laboratory Investigation

160

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SUMMARY:Loss of expression of the retinoblastoma gene (RB1) has been shown to occur in up to 25% of glioblastomas (WHO Grade IV). To elucidate the underlying mechanism, we assessed RB1 promoter hypermethylation using methylation-specific polymerase chain reaction and RB1 expression by immunohistochemistry in 35 primary (de novo) glioblastomas and in 21 secondary glioblastomas that had progressed from low-grade diffuse astrocytoma (WHO Grade II) or anaplastic astrocytoma (WHO Grade III). Promoter hypermethylation was significantly more frequent in secondary (9 of 21, 43%) than in primary glioblastomas (5 of 35, 14%; p ϭ 0.0258). There was a clear correlation between loss of RB1 expression and promoter hypermethylation. In the majority of glioblastomas with loss of RB1 expression, there was promoter hypermethylation (11 of 13, 85%), whereas 93% of tumors with RB1 expression had a normal RB1 gene status (p Ͻ 0.0001). In three glioblastomas, areas with and without RB1 expression were microdissected; promoter hypermethylation was detected only in areas lacking RB1 expression. In patients with multiple biopsies, methylation of the RB1 promoter was not detectable in the less malignant precursor lesions, ie, low-grade diffuse and anaplastic astrocytoma. These results indicate that promoter hypermethylation is a late event during astrocytoma progression and is the major mechanism underlying loss of RB1 expression in glioblastomas. (Lab Invest 2001, 81:77-82).

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“…The frequency of TSG inactivation by de novo methylation varies between TSGs and between cancers. Initially, epigenetic silencing of TSGs was reported as an alternative, but a minor mechanism of inactivation for TSGs such as RB1 and VHL (Greger et al, 1994;Herman et al, 1994). However, recently a new class of TSGs has been recognised for which epigenetic silencing is the overwhelming mechanism of inactivation and somatic mutations are rare.…”

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confidence: 99%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

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Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma

Cited by 161 publications

References 15 publications

Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

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