title: Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers.
abstract: The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P<.0001) but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence (P<.0001). However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany; General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Burdelski
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hube-Magg
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kluth
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany; General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Asmus
authors.initials: A
authors.lastname: Heumann
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: r.simon@uke.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Clauditz
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Büscheck
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wittmer
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hinsch
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Luebke
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobsen
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Beyer
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steuber
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Thederan
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Izbicki
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany; Department of Urology, Section for translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Wilczak
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D018450:Disease Progression; D019483:Disintegrins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D000071230:Transcriptional Regulator ERG / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019483:Disintegrins; D008565:Membrane Proteins; D015514:Oncogene Proteins, Fusion; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen; D051722:ADAM Proteins; C098660:ADAM15 protein, human