Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.


Type
Article
Change log
Authors
Kang, Eun Young 
Cheasley, Dane 
Wakefield, Matthew J 
da Cunha Torres, Michelle 
Abstract

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Description
Keywords
Adult, Australia, Biomarkers, Tumor, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Middle Aged, Mutation, Neoplasms, Cystic, Mucinous, and Serous, North America, Observer Variation, Ovarian Neoplasms, Predictive Value of Tests, Prognosis, Reproducibility of Results, Risk Assessment, Risk Factors, Tissue Array Analysis, Tumor Suppressor Protein p53, United Kingdom
Journal Title
Mod Pathol
Conference Name
Journal ISSN
0893-3952
1530-0285
Volume Title
34
Publisher
Elsevier BV
Rights
All rights reserved
Sponsorship
Cancer Research UK (22905)
Cancer Research UK (A22905)
Cancer Research UK (A15601)
KLG is supported by the Victorian Cancer Agency (MCRF15013) and the Australian National Health and Medical Research Council (APP1045783 and #628434). This study was supported by the Peter MacCallum Cancer Foundation. CS is supported by a University of Melbourne Postgraduate Scholarship. DDB is supported by National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044 and by the US National Cancer Institute U54 programme (U54CA209978-04). ELG and SHK are supported through P50 CA136393-10. The following cohorts that contributed to the GAMuT study were supported as follows: CASCADE: Supported by the Peter MacCallum Cancer Foundation AOCS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID400413 and ID400281). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in these research programs. OVCARE receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation. The Gynaecological Oncology Biobank at Westmead is a member of the Australasian Biospecimen Network-Oncology group, which was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. COEUR: This study uses resources provided by the Canadian Ovarian Cancer Research Consortium’s - COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l’Université de Montréal (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see http://www.tfri.ca/en/research/translational-research/coeur/coeur_biobanks.aspx). The following cohorts that contributed to OTTA were supported as follows: AOV: Canadian Institutes of Health Research (MOP-86727), Cancer Research Society (19319). BAV: ELAN Funds of the University of Erlangen-Nuremberg; DOV: NCI/NIH R01CA168758. Huntsman Cancer Foundation and the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014. HAW: U.S. National 19 Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; SEA: SEARCH team: Mitul Shah, Jennifer Alsopp, Mercedes Jiminez-Linan SEARCH funding: Cancer Research UK (C490/A16561), the Cancer Research UK Cambridge Cancer Centre and the National Institute for Health Research Cambridge Biomedical Research Centres. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. JBD: Cancer Research UK Institute Group Award UK A22905 and A15601; STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and årKampMotCancer foundation; TVA: Canadian Institutes of Health Research grant (MOP-86727) and NIH/NCI 1 R01CA160669- 01A1; VAN: M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. The Vancouver study cohort (TVAN) is supported by BC’s Ovarian Cancer Research team (OVCARE), the BC Cancer Foundation and The VGH+UBC Hospital Foundation. WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16.