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J Pathol Clin Res. 2018 Oct;4(4):250-261. doi: 10.1002/cjp2.109. Epub 2018 Sep 21.

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

Author information

1
Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
2
Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania.
3
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
4
School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, NSW, Australia.
5
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
6
Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
7
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
8
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
9
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
10
Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.
11
Department of Histopathology, Addenbrookes Hospital, Cambridge, UK.
12
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
13
Gynaecological Cancer Research Centre, Women's Cancer, Institute for Women's Health, University College London, London, UK.
14
Medical Oncology Service, Hospital Universitario Funcación Alcorcón, Alcorcón, Spain.
15
Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
16
Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
17
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
18
Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
19
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
20
Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, NSW, Australia.
21
University of Western Sydney at Westmead Hospital, Westmead, NSW, Australia.
22
Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
23
The Crown Princess Mary Cancer Centre Westmead, Sydney-West Cancer Network, Westmead Hospital, Sydney, NSW, Australia.
24
Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
25
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, AB, Canada.
26
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
27
John A. Burns School of Medicine, Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, HI, USA.
28
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
29
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
30
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
31
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
32
Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
33
Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
34
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
35
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
36
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
37
Division of Bioscience, Brunel University, London, UK.
38
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
39
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
40
Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
41
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
42
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
43
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
44
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
45
Department of Environmental Medicine, Division of Nutritional Epidemiology, Karolinska Institutet, Stockholm, Sweden.
46
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
47
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
48
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
49
Institute of Pathology, Tübingen University Hospital, Tübingen, Germany.
50
British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, Vancouver, BC, Canada.
51
Department of Epidemiology, University of Washington, Seattle, WA, USA.
52
Department of Research, Cancer Genomics and Genetics, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
53
Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
54
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
55
Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
56
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
57
Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
58
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
59
Department of Genetics and Genomic Sciences, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
60
Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK.
61
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
62
Department of Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
63
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
64
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
65
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
66
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
67
Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
68
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
69
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
70
Medical Oncology Service, HM Hospitales - Centro Integral Oncológico HM Clara Campal, Madrid, Spain.
71
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
72
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
73
Pathology Department, Fundación Jiménez Díaz-Quiron Salud, Madrid, Spain.
74
Department of Histopathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
75
Pathology Department, IRYCIS, CIBERONC, Universidad de Alcalá, Hospital Universitario Ramón y Cajal, Madrid, Spain.
76
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
77
Alberta Health Services-Cancer Care, Calgary, AB, Canada.
78
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
79
University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
80
Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada.
81
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
82
Department of Molecular Oncology, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
83
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia.

Abstract

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

KEYWORDS:

RT-QPCR; immunocytochemistry; ovary

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