PMID- 26479291
OWN - NLM
STAT- MEDLINE
DCOM- 20160606
LR  - 20220316
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Linking)
VI  - 122
IP  - 1
DP  - 2016 Jan 1
TI  - RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated 
      pleomorphic sarcomas.
PG  - 99-107
LID - 10.1002/cncr.29733 [doi]
AB  - 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.
CI  - (c) 2015 American Cancer Society.
FAU - Serrano, Cesar
AU  - Serrano C
AD  - Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall 
      d'Hebron University Hospital, Barcelona, Spain.
FAU - Romagosa, Cleofe
AU  - Romagosa C
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Hernandez-Losa, Javier
AU  - Hernandez-Losa J
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Simonetti, Sara
AU  - Simonetti S
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Valverde, Claudia
AU  - Valverde C
AD  - Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall 
      d'Hebron University Hospital, Barcelona, Spain.
FAU - Moline, Teresa
AU  - Moline T
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Somoza, Rosa
AU  - Somoza R
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Perez, Manuel
AU  - Perez M
AD  - Department of Orthopedic Surgery, Vall d'Hebron University Hospital, Barcelona, 
      Spain.
FAU - Velez, Roberto
AU  - Velez R
AD  - Department of Orthopedic Surgery, Vall d'Hebron University Hospital, Barcelona, 
      Spain.
FAU - Verges, Ramona
AU  - Verges R
AD  - Department of Radiotherapy, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Dominguez, Rosa
AU  - Dominguez R
AD  - Department of Radiology, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Carles, Joan
AU  - Carles J
AD  - Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Vall 
      d'Hebron University Hospital, Barcelona, Spain.
FAU - Ramon Y Cajal, Santiago
AU  - Ramon Y Cajal S
AD  - Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151019
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (KRAS protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
CIN - Cancer. 2016 Jan 1;122(1):17-9. PMID: 26479175
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Female
MH  - Humans
MH  - *MAP Kinase Signaling System
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinases/genetics/*metabolism
MH  - Prognosis
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*metabolism
MH  - Sarcoma/*enzymology/genetics/pathology
MH  - Signal Transduction
OTO - NOTNLM
OT  - KRAS
OT  - RAS/mitogen-activated protein kinases (MAPK) pathway
OT  - outcomes
OT  - phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) 
      pathway
OT  - undifferentiated pleomorphic sarcoma
EDAT- 2015/10/20 06:00
MHDA- 2016/06/09 06:00
CRDT- 2015/10/20 06:00
PHST- 2015/04/29 00:00 [received]
PHST- 2015/07/06 00:00 [revised]
PHST- 2015/07/24 00:00 [accepted]
PHST- 2015/10/20 06:00 [entrez]
PHST- 2015/10/20 06:00 [pubmed]
PHST- 2016/06/09 06:00 [medline]
AID - 10.1002/cncr.29733 [doi]
PST - ppublish
SO  - Cancer. 2016 Jan 1;122(1):99-107. doi: 10.1002/cncr.29733. Epub 2015 Oct 19.