Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers

TY - JOUR

T1 - Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers

AU - Burdelski, Christoph

AU - Fitzner, Michael

AU - Hube-Magg, Claudia

AU - Kluth, Martina

AU - Heumann, Asmus

AU - Simon, Ronald

AU - Krech, Till

AU - Clauditz, Till

AU - Büscheck, Franziska

AU - Steurer, Stefan

AU - Wittmer, Corinna

AU - Hinsch, Andrea

AU - Luebke, Andreas M

AU - Jacobsen, Frank

AU - Minner, Sarah

AU - Tsourlakis, Maria Christina

AU - Beyer, Burkhard

AU - Steuber, Thomas

AU - Thederan, Imke

AU - Sauter, Guido

AU - Izbicki, Jakob

AU - Schlomm, Thorsten

AU - Wilczak, Waldemar

N1 - Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.neo.2017.01.005

DO - 10.1016/j.neo.2017.01.005

M3 - SCORING: Journal article

C2 - 28282546

VL - 19

SP - 279

EP - 287

JO - NEOPLASIA

JF - NEOPLASIA

SN - 1476-5586

IS - 4

ER -