title: RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas.
abstract: BACKGROUND
  Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of 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 considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome.
  
  
  METHODS
  Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor 4E (eIF-4E), S6-RP, and ERK 1/2, together with total forms of 4E-BP1 and eIF-4E, were assessed using immunohistochemistry in paraffin-embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well.
  
  
  RESULTS
  Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor.
  
  
  CONCLUSIONS
  The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome.
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Serrano
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Cleofé
authors.initials: C
authors.lastname: Romagosa
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Simonetti
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Valverde
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moliné
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Somoza
authors.affiliation: Department of Orthopedic Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pérez
authors.affiliation: Department of Orthopedic Surgery, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Vélez
authors.affiliation: Department of Radiotherapy, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Ramona
authors.initials: R
authors.lastname: Vergés
authors.affiliation: Department of Radiology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Domínguez
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Carles
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; RAS/mitogen-activated protein kinases (MAPK) pathway; outcomes; phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathway; undifferentiated pleomorphic sarcoma