High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer.
γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p< 0.0001), advanced pathological tumor stage, and high Gleason grade (p< 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p< 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN,p≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p< 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. n.melling@uke.de.|General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. n.melling@uke.de.
Nathaniel
N
Melling
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. masoudrashed@msn.com.
Masoud
M
Rashed
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. cor.schroeder@uke.de.|General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. cor.schroeder@uke.de.
Cornelia
C
Schroeder
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. c.hube@uke.de.
Claudia
C
Hube-Magg
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. m.kluth@uke.de.
Martina
M
Kluth
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. d.lang@uke.de.
Dagmar
D
Lang
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. r.simon@uke.de.
Ronald
R
Simon
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. c.koop@uke.de.
Christina
C
Möller-Koop
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. s.steurer@uke.de.
Stefan
S
Steurer
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. g.sauter@uke.de.
Guido
G
Sauter
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. f.jacobsen@uke.de.
Frank
F
Jacobsen
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. f.buescheck@uke.de.
Franziska
F
Büscheck
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. c.wittmer@uke.de.
Corinna
C
Wittmer
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. t.clauditz@uke.de.
Till
T
Clauditz
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. t.krech@uke.de.
Till
T
Krech
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. m.tsourlakis@uke.de.
Maria Christina
MC
Tsourlakis
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. s.minner@uke.de.
Sarah
S
Minner
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. hhuland@uke.de.
Hartwig
H
Huland
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. graefen@uke.de.
Markus
M
Graefen
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. budaeus@uke.de.
Lars
L
Budäus
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. i.thederan@uke.de.
Imke
I
Thederan
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. gsalomon@uke.de.
Georg
G
Salomon
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. t.schlomm@uke.de.|Department of Urology, Section for translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. t.schlomm@uke.de.
Thorsten
T
Schlomm
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany. w.wilczak@uke.de.
Waldemar
W
Wilczak
D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D000072662:Margins of Excision; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality* / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D017384:Sequence Deletion; D000071230:Transcriptional Regulator ERG / Q000172:deficiency* / Q000235:genetics; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D000071230:Transcriptional Regulator ERG; D011623:gamma-Glutamyl Hydrolase; D017430:Prostate-Specific Antigen
ERG; GGH; TMA; deletion; folic acid; multivariate models; prognostic factors; prostate cancer; tissue biomarkers