Bei verschiedenen Tumordispositionserkrankungen mit pleiotropem Manifestationsspektrum ist das Auge mit involviert. Unter den monogen erblichen Tumorerkrankungen ist aus klinischer Sicht das erbliche ...Retinoblastom am wichtigsten. Das zur Erklärung seiner Entstehung entwickelte 2-Schritt-Mutationsmodell war auch für die Aufklärung anderer dominanter Tumordispositionen wegweisend. Bei den meisten anderen erblichen Krebserkrankungen sind die Manifestationen im Bereich des Auges für den Krankheitsverlauf nicht relevant, können aber zur Diagnose führen. Dies gilt insbesondere für das retinale kapillare Hämangiom bei Patienten mit einer Von-Hippel-Lindau-Erkrankung. Für die Entstehung des Aderhautmelanoms, des häufigsten bösartigen Augentumors, gibt es keinen Hinweis auf eine monogene Disposition. Allerdings lassen epidemiologische Daten vermuten, dass für seine Entstehung genetische Faktoren eine Rolle spielen. Die Prognose bei diesem Tumor ist eng mit einem somatischen genetischen Marker, der Monosomie 3, verbunden.
Es el tumor más frecuente del niño. Su incidencia es de 1 x 20,000 nacimientos, 2/3 de la forma son unilaterales y la edad promedio del diagnóstico es de dos años. Tiene una historia genética ...bastante conocida en la que la anomalía se establece en el gen RBI, que está ubicado en el cromosoma 13. El diagnóstico precoz se basa en dos signos reveladores que son: la leucocoria y el estrabismo. El tratamiento más común es la enucleación seguida de quimioterapia y el estrabismo. El tratamiento más común en la enucleación seguida de quimioterapia adyuvante. Los tratamientos conservadores se reservan para casos incipientes y en Centros especializados.
To determine the correlation between the International Classification of Retinoblastoma (ICRB) and histopathologic high-risk retinoblastoma.
Retrospective study.
A total of 519 patients.
Primary ...enucleation.
High-risk retinoblastoma, metastasis, and death.
Of 519 primarily enucleated eyes, 87 (17%) were classified as group D and 432 (83%) were classified as group E on the basis of the ICRB. High-risk retinoblastoma was identified in 23% (117/519) of enucleated eyes, including 17% (15/87) group D and 24% (102/432) group E eyes. High-risk histopathologic features of retinoblastoma included anterior chamber involvement (5/15 33% group D eyes, 31/102 30% group E eyes), isolated massive posterior uveal invasion ≥ 3 mm (7/15 47% group D eyes, 22/102 22% group E eyes), isolated post-laminar optic nerve invasion (2/15 13% group D eyes, 46/102 45% group E eyes), and any combination of posterior uveal invasion and optic nerve involvement (7/15 47% group D eyes, 37/102 36% group E eyes). On logistic regression analysis, massive posterior uveal invasion ≥ 3 mm was more common in group D eyes (P = 0.0442), and post-laminar optic nerve invasion was more common in group E eyes (P = 0.0390). Of 117 patients with high-risk retinoblastoma, systemic adjuvant chemotherapy was administered in 83 patients (71%). Systemic metastasis developed in 0% (0/15) of those with high-risk group D retinoblastoma and 10% (10/102) of those with high-risk group E retinoblastoma over a mean follow-up period of 78 months (median, 62 months; range, 1-419 months). There was no metastasis in any patient (n = 402) classified with non-high-risk retinoblastoma. Of the 10 patients who developed metastasis, 4 had received prior adjuvant chemotherapy and 6 had no prior adjuvant chemotherapy. There was no metastasis in high-risk patients treated with vincristine sulphate, etoposide phosphate, and carboplatin (VEC). Death from metastasis occurred in 4% of high-risk patients (5/117).
On the basis of the ICRB, 17% of group D and 24% of group E eyes are at increased risk for metastatic disease. In this study, 8% of patients developed metastasis. There was no metastasis in any patient classified with non-high-risk retinoblastoma.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
The retinoblastoma protein (RB) restricts cell cycle gene expression and entry into the cell cycle. The RB-related protein p130 forms the DREAM (DP, RB-like, E2F, and MuvB) complex and contributes to ...repression of cell cycle-dependent genes during quiescence. Although both RB and DREAM bind and repress an overlapping set of E2F-dependent gene promoters, it remains unclear whether they cooperate to restrict cell cycle entry. To test the specific contributions of RB and DREAM, we generated RB and p130 knockout cells in primary human fibroblasts. Knockout of both p130 and RB yielded higher levels of cell cycle gene expression in G0 and G1 cells compared to cells with knockout of RB alone, indicating a role for DREAM and RB in repression of cell cycle genes. We observed that RB had a dominant role in E2F-dependent gene repression during mid to late G1 while DREAM activity was more prominent during G0 and early G1. Cyclin D-Cyclin-Dependent Kinase 4 (CDK4)-dependent phosphorylation of p130 occurred during early G1, and led to the release of p130 and MuvB from E2F4 and decreased p130 and MuvB binding to cell cycle promoters. Specific inhibition of CDK4 activity by palbociclib blocked DREAM complex disassembly during cell cycle entry. In addition, sensitivity to CDK4 inhibition was dependent on RB and an intact DREAM complex in both normal cells as well as in palbociclib-sensitive cancer cell lines. Although RB knockout cells were partially resistant to CDK4 inhibition, RB and p130 double knockout cells were significantly more resistant to palbociclib treatment. These results indicate that DREAM cooperates with RB in repressing E2F-dependent gene expression and cell cycle entry and supports a role for DREAM as a therapeutic target in cancer.
PDF
