p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer.
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.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Patrick
P
Lebok
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Magdalena
M
Roming
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Martina
M
Kluth
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christina
C
Koop
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Cansu
C
Özden
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Berivan
B
Taskin
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Khakan
K
Hussein
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Annette
A
Lebeau
Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Isabell
I
Witzel
Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Linn
L
Wölber
Department of Gynecology, Regio Clinic Pinneberg, Pinneberg, Germany.
Stefan
S
Geist
Department of Gynecology, Regio Clinic Pinneberg, Pinneberg, Germany.
Peter
P
Paluchowski
Department of Gynecology, Regio Clinic Elmshorn, Elmshorn, Germany.
Christian
C
Wilke
Department of Gynecology, Clinical Centre Itzehoe, Itzehoe, Germany.
Uwe
U
Heilenkötter
Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Volkmar
V
Müller
Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Barbara
B
Schmalfeldt
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ronald
R
Simon
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Guido
G
Sauter
Department of Pathology, Basel University Clinics, Basel, Switzerland.
Luigi
L
Terracciano
Institute of Pathology, Clinical Centre Osnabrück, Osnabrück, Germany.
Rainer Horst
RH
Krech
Breast Centre Osnabrück, Osnabrück, Germany.
Albert
A
von der Assen
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Eike
E
Burandt
D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D049109:Cell Proliferation; D025063:Chromosome Disorders / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D060787:Neoplasm Grading; D010641:Phenotype; D016016:Proportional Hazards Models; D012307:Risk Factors; D046888:Tissue Array Analysis; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16
9p21 deletion; CDKN2A; TMA; breast cancer; p16 expression