p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer - PubMed (original) (raw)

. 2016 Dec 6;7(49):81322-81331.

doi: 10.18632/oncotarget.13227.

Magdalena Roming 1, Martina Kluth 1, Christina Koop 1, Cansu Özden 1, Berivan Taskin 1, Khakan Hussein 1, Annette Lebeau 1, Isabell Witzel 2, Linn Wölber 2, Stefan Geist 3, Peter Paluchowski 3, Christian Wilke 4, Uwe Heilenkötter 5, Volkmar Müller 2, Barbara Schmalfeldt 2, Ronald Simon 1, Guido Sauter 1, Luigi Terracciano 6, Rainer Horst Krech 7, Albert von der Assen 8, Eike Burandt 1

Affiliations

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

Patrick Lebok et al. Oncotarget. 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.

Keywords: 9p21 deletion; CDKN2A; TMA; breast cancer; p16 expression.

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CONFLICTS OF INTEREST

We certify that there is no actual or potential conflicts of interest in relation to this article.

Figures

Figure 1

Figure 1. Representative images of p16 immunostaining with (A) negative, (B) weak, (C) moderate, and (D) strong staining and examples of FISH findings using the 9p21 deletion probe

(E) Heterozygous deletion as indicated by the lack of one orange 9p21 signal and two green centromere 9 signals, (F) Homozygous deletion as indicated by the complete lack of orange 9p21 signals in the tumor cell, (G) Normal 9p21 copy numbers as indicated by two orange 9p21 signals and two green centromere 9 signals.

Figure 2

Figure 2. Association between p16 expression and raw survival in (A) all cancers, (B) no special type cancers, (C) nodal negative cancers, (D) nodal positive cancers, and (E) triple negative cancers

Association between 9p21 deletion and raw survival in (F) all cancers, (G) no special type cancers, (H) nodal negative cancers, (I) nodal positive cancers, and (J) triple negative cancers.

Figure 3

Figure 3. Association between 9p21 deletion (FISH) and p16 expression (IHC)

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