Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers.
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Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers. / Müller, Juliane; Ehlers, Arne; Burkhardt, Lia; Sirma, Hüseyin; Steuber, Thomas; Graefen, Markus; Sauter, Guido; Minner, Sarah Jane Pauline; Simon, Ronald; Schlomm, Thorsten; Michl, Uwe.
in: INT J CANCER, Jahrgang 132, Nr. 6, 6, 2013, S. 1333-1340.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers.
AU - Müller, Juliane
AU - Ehlers, Arne
AU - Burkhardt, Lia
AU - Sirma, Hüseyin
AU - Steuber, Thomas
AU - Graefen, Markus
AU - Sauter, Guido
AU - Minner, Sarah Jane Pauline
AU - Simon, Ronald
AU - Schlomm, Thorsten
AU - Michl, Uwe
PY - 2013
Y1 - 2013
N2 - Prevalence and clinical significance of mammalian target of rapamycin (mTOR) phosphorylation at the serine 2448 is disputed in prostate cancer. A tissue microarray containing 3,261 prostate cancers and 49 normal prostate samples with clinical follow-up data was analyzed for p(Ser2448)-mTOR expression by immunohistochemistry. Moderate to strong p(Ser2448)-mTOR staining was found in all (n = 49) normal prostate tissues, but was lost in 24% or weak in 29% cancers. Moderate and strong staining was found in 36 and 11% of tumors. Loss of p(Ser2448)-mTOR staining was significantly linked to advanced stage (p = 0.0027), high-grade (p = 0.0045), nodal positive cancers (p = 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p = 0.0016), lack of Ets-related gene (ERG) fusion (p < 0.0001), reduced androgen receptor expression (p < 0.0001 each) and increased cell proliferation (p = 0.0092) in all cancers and in the subset of ERG-fusion-positive cancers. Loss of p(Ser2448)-mTOR expression was linked to tumor metastasis (p = 0.0275) in ERG-fusion-positive cancers only. Molecular subset analysis using pre-existing phosphatase and tensin homolog (PTEN) deletion data revealed that loss of p(Ser2448) -mTOR expression is of prognostic relevance and defines a subpopulation of PTEN-deleted and ERG-fusion-positive cancers with a particular poor outcome. The results of our study strongly suggest that loss of p(Ser2448)-mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p(Ser2448)-mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti-mTOR therapies.
AB - Prevalence and clinical significance of mammalian target of rapamycin (mTOR) phosphorylation at the serine 2448 is disputed in prostate cancer. A tissue microarray containing 3,261 prostate cancers and 49 normal prostate samples with clinical follow-up data was analyzed for p(Ser2448)-mTOR expression by immunohistochemistry. Moderate to strong p(Ser2448)-mTOR staining was found in all (n = 49) normal prostate tissues, but was lost in 24% or weak in 29% cancers. Moderate and strong staining was found in 36 and 11% of tumors. Loss of p(Ser2448)-mTOR staining was significantly linked to advanced stage (p = 0.0027), high-grade (p = 0.0045), nodal positive cancers (p = 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p = 0.0016), lack of Ets-related gene (ERG) fusion (p < 0.0001), reduced androgen receptor expression (p < 0.0001 each) and increased cell proliferation (p = 0.0092) in all cancers and in the subset of ERG-fusion-positive cancers. Loss of p(Ser2448)-mTOR expression was linked to tumor metastasis (p = 0.0275) in ERG-fusion-positive cancers only. Molecular subset analysis using pre-existing phosphatase and tensin homolog (PTEN) deletion data revealed that loss of p(Ser2448) -mTOR expression is of prognostic relevance and defines a subpopulation of PTEN-deleted and ERG-fusion-positive cancers with a particular poor outcome. The results of our study strongly suggest that loss of p(Ser2448)-mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p(Ser2448)-mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti-mTOR therapies.
KW - Humans
KW - Male
KW - Prognosis
KW - Disease Progression
KW - Proportional Hazards Models
KW - Gene Deletion
KW - Phosphorylation
KW - PTEN Phosphohydrolase/genetics
KW - Trans-Activators/genetics
KW - Gene Fusion
KW - Prostatic Neoplasms/chemistry/etiology/genetics/pathology
KW - TOR Serine-Threonine Kinases/analysis/physiology
KW - Humans
KW - Male
KW - Prognosis
KW - Disease Progression
KW - Proportional Hazards Models
KW - Gene Deletion
KW - Phosphorylation
KW - PTEN Phosphohydrolase/genetics
KW - Trans-Activators/genetics
KW - Gene Fusion
KW - Prostatic Neoplasms/chemistry/etiology/genetics/pathology
KW - TOR Serine-Threonine Kinases/analysis/physiology
M3 - SCORING: Journal article
VL - 132
SP - 1333
EP - 1340
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 6
M1 - 6
ER -
