Abstract B70: p16 and 9p21 deletion are largely unrelated but linked to unfavorable tumor phenotype in breast cancer

Abstract

Abstract Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, has been linked to unfavorable tumor phenotype and poor patient outcome in breast cancer. To better understand these seemingly contradictory observations, and the prognostic impact of p16 expression and 9p21 deletion in breast cancer, we analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a CDKN2A-specific probe and by p16 immunohistochemistry. p16 immunostaining was typically uniform and considered weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 analyzable cancers. Strong p16 staining was significantly 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 shortened 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 significantly 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 also worse in p16 deleted than in undeleted cancers but this difference did not reach statistical significance (p=0,0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions. However, a striking difference in p16 expression was not found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p=0.0256). In conclusion, p16 expression is unrelated to 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. Citation Format: Patrick Lebok, Magdalena Roming, Martina Kluth, Christina Koop, Cansu Oezden, Brevian Taskin, Khakan Hussein, Anette Lebeau, Isabell Witzel, Sven Mahner, Stefan Geist, Peter Paluchowski, Christian Wilke, Uwe Heilenkoetter, Volkmar Mueller, Ronald Simon, Guido Sauter, Luigi Terracciano, Rainer Krech, Albert von der Assen, Eike Burandt. p16 and 9p21 deletion are largely unrelated but linked to unfavorable tumor phenotype in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B70.