Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression

Xu, Hong‐Ji; Cairns, Paul; Hu, Shi‐Xue; Knowles, Margaret A.; Benedict, William F.

doi:10.1002/ijc.2910530513

Cited by 136 publications

(86 citation statements)

References 11 publications

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“…Loss of RB1 expression has been found to correlate well with LOH at the RB1 locus in hepatocellular carcinomas (Zhang et al, 1994), bladder carcinomas (Xu et al, 1993), and malignant neuroendocrine lung carcinomas (Gouyer et al, 1994). However, it did not correlate with LOH at the RB1 locus in other tumors, including glioblastomas (Burns et al, 1998;Ueki et al, 1996), pituitary tumors (Pei et al, 1995;Simpson et al, 1999), and carcinomas of the breast (Borg et al, 1992), prostate (Cooney et al, 1996), ovary (Dodson et al, 1994;Kim et al, 1994), and head and neck (Yoo et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

Nakamura

Yonekawa

Kleihues

et al. 2001

Laboratory Investigation

158

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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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Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

Nakamura

Yonekawa

Kleihues

et al. 2001

Laboratory Investigation

158

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“…37 Inability to detect pRb immunohistochemically is associated with increased tumor grade and stage, especially muscle invasion. 38 Additionally, since a phosphorylated pRb cannot bind E2F-1, hyperphosphorylated pRb, which can be identified immunohistochemically as intense nuclear staining, carries with it a similarly ominous prognosis as absence of Rb staining. 39,40 The p53 Tumor Suppressor Gene: The p53 gene encodes a 53kDa transcription factor with a critical role in DNA repair and apoptosis.…”

Section: Retinoblastoma Tumor Suppressor Genementioning

confidence: 99%

Molecular Mechanisms and Pathways in Bladder Cancer Development and Progression

Jung

Messing

2000

Cancer Control

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Background: The basis for bladder cancer development and progression is complex and involves genetic abnormalities. These abnormalities yield phenotypic changes that allow normal transitional cells to becomeity of these new cases, approximately 75%, are limited to the mucosa (stage Ta or Tis) and lamina propria (T1) at presentation, and most of these tumors can be removed by transurethral resection. Recurrence rates are high (30% to 85%), and 10% to 30% of "superficial" tumors (T1 or less) will subsequently progress to muscle invasive disease (stages T2-T4), which has a poorer prognosis. 2 For the remaining 25%, the initial presentation involves muscle invasive disease that will usually relapse with metastases (as well as localized disease persistence) within a median of 2 years if managed only by transurethral resection and intravesical therapy. 3 These data support the heterogeneous nature and malignant potential of transitional cell carcinoma

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“…Inactivation of the RB gene is a common event in bladder cancer (Horowitz et al, 1990;Ishikawa et al, 1991;Xu et al, 1993) and is seen more frequently in higher grade and invasive stage tumors (Xu et al, 1993). Moreover, loss of RB function has been associated with progression to invasive disease and decreased survival (Cordon-Cardo et al, 1992;Logothetis et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

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Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression

Cited by 136 publications

References 11 publications

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

Promoter Hypermethylation of the RB1 Gene in Glioblastomas

Molecular Mechanisms and Pathways in Bladder Cancer Development and Progression

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

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