Oncotarget

Research Papers:

p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer

Patrick Lebok _, Magdalena Roming, Martina Kluth, Christina Koop, Cansu Özden, Berivan Taskin, Khakan Hussein, Annette Lebeau, Isabell Witzel, Linn Wölber, Stefan Geist, Peter Paluchowski, Christian Wilke, Uwe Heilenkötter, Volkmar Müller, Barbara Schmalfeldt, Ronald Simon, Guido Sauter, Luigi Terracciano, Rainer Horst Krech, Albert von der Assen and Eike Burandt

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Oncotarget. 2016; 7:81322-81331. https://doi.org/10.18632/oncotarget.13227

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Abstract

Patrick Lebok1,*, Magdalena Roming1,*, Martina Kluth1, Christina Koop1, Cansu Özden1, Berivan Taskin1, Khakan Hussein1, Annette Lebeau1, Isabell Witzel2, Linn Wölber2, Stefan Geist3, Peter Paluchowski3, Christian Wilke4, Uwe Heilenkötter5, Volkmar Müller2, Barbara Schmalfeldt2, Ronald Simon1, Guido Sauter1, Luigi Terracciano6, Rainer Horst Krech7, Albert von der Assen8, Eike Burandt1

1Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Department of Gynecology, Regio Clinic Pinneberg, Pinneberg, Germany

4Department of Gynecology, Regio Clinic Elmshorn, Elmshorn, Germany

5Department of Gynecology, Clinical Centre Itzehoe, Itzehoe, Germany

6Department of Pathology, Basel University Clinics, Basel, Switzerland

7Institute of Pathology, Clinical Centre Osnabrück, Osnabrück, Germany

8Breast Centre Osnabrück, Osnabrück, Germany

*These authors contributed equally to this work

Correspondence to:

Partick Lebok, email: [email protected]

Keywords: breast cancer, 9p21 deletion, TMA, p16 expression, CDKN2A

Received: May 04, 2016     Accepted: November 01, 2016     Published: November 09, 2016

ABSTRACT

Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, is linked to unfavorable tumor phenotype and poor prognosis in breast cancer. To better understand these contradictory observations, and to clarify the prognostic impact of p16 expression and 9p21 deletion, a tissue microarray (TMA) with 2,197 breast cancers was analyzed by fluorescence in-situ hybridization and immunohistochemistry (FISH) for 9p21 deletion and p16 expression. p16 immunostaining was weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 evaluable cancers. Strong p16 staining was linked to advanced tumor stage (p = 0.0003), high-grade (p < 0.0001), high tumor cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p < 0.0001 each), and shorter overall survival (p = 0.0038). 9p21 deletion was found in 15.3% of 1,089 analyzable breast cancers, including 1.7% homozygous and 13.6% heterozygous deletions. 9p21 deletion was linked to adverse tumor features, including high-grade (p < 0.0001) and nodal positive cancers (p = 0.0063), high cell proliferation (p < 0.0001), negative hormone receptor (ER/PR) status (p ≤ 0.0006), and HER2 amplification (p = 0.0078). Patient outcome was worse in 9p21 deleted than in undeleted cancers (p = 0.0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions, but no difference in p16 expression was found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p = 0.0256). In summary, p16 expression is unrelated to partial 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High-level p16 expression is a strong predictor of unfavorable disease course in breast cancer.


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