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Published on: April 7, 2017
Altered patterns of RB expression define groups of soft tissue sarcoma patients with distinct biological and clinical
D Polsky1, S Mastorides, D Kim
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA. david.polsky@med.nyu.edu
Background:
Function of the retinoblastoma tumor suppressor protein (pRB) may be compromised at a genetic level by gene loss or mutation or at a post-translational level by hyperphosphorylation. In this study, we examined adult soft tissue sarcomas (ASTS) to determine if alterations of pRB were associated with distinct patterns of pRB expression and clinical outcome.
Design:
We investigated 86 ASTS patients using monoclonal antibodies that distinguish between hyperphosphorylated and underphosphorylated pRB products. We also used microsatellite analysis to investigate the genetic status of the RB locus. We correlated pRB alterations with proliferative activity, and with clinicopathological outcomes.
Results:
Altered patterns of pRB expression are common in ASTS occurring in 84% of cases, and it is significantly associated with proliferative activity (p<0.001). Patients whose tumors either lack expression of pRB, or express hyperphosphorylated forms of pRB, have poor survivals compared to patients whose tumors exhibit a normal, underphosphorylated pattern of pRB expression (p=0.03). In addition, 63% of cases lacking expression of pRB showed loss-of-heterozygosity at the locus.
Conclusions:
Inactivation of pRB is common in adult STS, which may be due to either gene loss or post-translational modification, namely hyper-phosphorylation. Both mechanisms are associated with tumor cell proliferation and poor survival.
Insights
Alterations in the retinoblastoma tumor suppressor protein (pRB) are frequent in adult soft tissue sarcomas (ASTS). Both genetic inactivation and hyperphosphorylation of pRB correlate with increased tumor proliferation and poorer patient survival outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The retinoblastoma tumor suppressor protein (pRB) plays a critical role in cell cycle regulation.
- pRB function can be impaired through genetic alterations (loss or mutation) or post-translational modifications like hyperphosphorylation.
- Adult soft tissue sarcomas (ASTS) are a diverse group of cancers where pRB status may influence disease progression.
Purpose of the Study:
- To investigate the frequency and nature of pRB alterations in ASTS.
- To determine the association between pRB alterations, tumor proliferative activity, and patient clinical outcomes.
- To explore the relationship between genetic status of the RB locus and pRB expression patterns.
Main Methods:
- Analysis of 86 adult soft tissue sarcoma (ASTS) patient tumors.
- Utilized monoclonal antibodies to differentiate between hyperphosphorylated and underphosphorylated pRB forms.
- Employed microsatellite analysis to assess the genetic integrity of the RB locus.
Main Results:
- Altered pRB expression patterns were observed in 84% of ASTS cases.
- pRB alterations significantly correlated with increased tumor cell proliferation (p<0.001).
- Patients with absent or hyperphosphorylated pRB expression showed significantly poorer survival (p=0.03) compared to those with normal pRB patterns. Loss-of-heterozygosity at the RB locus was found in 63% of tumors lacking pRB expression.
Conclusions:
- Inactivation of pRB is a common event in adult soft tissue sarcomas (ASTS).
- Both genetic loss and post-translational hyperphosphorylation contribute to pRB inactivation in ASTS.
- These mechanisms of pRB inactivation are linked to increased tumor proliferation and adverse clinical outcomes, highlighting pRB as a potential therapeutic target.
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01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...