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RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas
César Serrano1, Cleofé Romagosa2, Javier Hernández-Losa2
1Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Cancer
|October 20, 2015
Summary
The RAS/MAPK and PI3K/mTOR pathways are activated in most undifferentiated pleomorphic sarcoma (UPS) cases. RAS/MAPK pathway activation independently predicts a worse outcome in UPS patients, highlighting its potential as a prognostic biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Undifferentiated pleomorphic sarcoma (UPS) is the most common soft tissue sarcoma but remains poorly understood clinically and molecularly.
- Its complexity lacks specific prognostic or predictive biomarkers.
- The RAS/mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are key in sarcoma but their role in UPS is unclear.
Purpose of the Study:
- To investigate the activation status of the RAS/MAPK and PI3K/mTOR pathways in UPS.
- To determine if pathway activation correlates with patient outcomes.
Main Methods:
- Retrospective review of UPS patient records (2000-2009).
- Immunohistochemistry assessed phosphorylation and total protein levels of key pathway components (4E-BP1, eIF-4E, S6-RP, ERK 1/2).
- Mutational analysis for common oncogenic mutations in KRAS, NRAS, BRAF, and PIK3CA.
Main Results:
- RAS/MAPK and PI3K/mTOR pathways were activated in over 80% of UPS cases.
- Hyperactivation of the RAS/MAPK pathway (phosphorylated ERK 1/2) independently predicted increased risk of recurrence and reduced overall survival.
- A KRAS A146V mutation was found in only one tumor.
Conclusions:
- The RAS/MAPK and PI3K/mTOR pathways are frequently activated in UPS.
- RAS/MAPK pathway activation identifies a subgroup of UPS patients with a poorer prognosis, suggesting its utility as a biomarker.
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