Publication: p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.
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Abstract
Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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Acknowledgements For all participating studies, the authors thank all the women who participated in research, study staff, study participants, doctors, nurses, health care providers, and health information sources who have contributed to the study. The authors thank Shuhong Liu and Young Ou from the Anatomical Pathology Research Laboratory at the University of Calgary for performing mmunohistochemistry, and Thomas Kryton, image specialist, for compiling the composite figures. The authors thank the Australian Ovarian Cancer Study (AOCS) Group that can be found at . The study was funded by Alberta Precision Laboratory research support fund (RS17-601, RS19-609, RS10-526). AOCS 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 Foundation of Western Australia, the Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC; ID199600, ID400413, and ID400281). AOCS gratefully acknowledges additional support from the Peter MacCallum Foundation and Ovarian Cancer Australia (OCA); AOV: Canadian Institutes of Health Research (MOP-86727), we thank Mie Konno, Michelle Darago, Faye Chambers; BAV: ELAN Funds of the University of Erlangen-Nuremberg; BGS: Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre; BRZ: Brazilian National Council for Scientific and Technological Development, grant No. 478416/2009-1; CAL: Cancer Research Society (19319) and CLS Internal Research support RS14-508; CNI: CNI funded by Instituto de Salud Carlos Tercero (AES grant PI19/01730) and Fondo Europeo de Desarrollo Regional, FEDER. Instituto de Salud Carlos III (PI 12/01319); Ministerio de Economia y Competitividad (SAF2012). AO is partially funded by FIS PI19/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER); DOV: NCI/NIH R01 CA168758, NCI/NIH R01 CA112523, and NCI/NIH R01 CA087538. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH; GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01GB9401) and the German Cancer Research Center (DKFZ); HAW: US National Institutes of Health (R01-CA58598, N01-CN-55424, and N01-PC-67001); HOP: Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, MO1-RR000056). This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource, which is supported in part by award P30CA047904; LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAY: National Institutes of Health (R01-CA122443, R01-CA243483, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; POC: Pomeranian Medical University; SEA: Cancer Research UK C490/A16561, the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Cambridge Cancer Centre. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve; STA: National Institutes of Health (U01-CA71966, U01-CA69417); SWE: Swedish Cancer Foundation (CAN 2018/384); TVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; UKO: The UKOPS study was funded by The Eve Appeal (the Oak Foundation) with contribution to U. Menon and A. Gentry-Maharaj's salary through MRC core funding (MC_UU_00004/01) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre; VAN: BC's Gynecological Cancer Research Team (OVCARE) receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 and ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 and 15/RIG/1-16. The Westmead GynBiobank acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW. SJR is supported by National Health and Medical Research Council of Australia (NHMRC) grant APP2009840. The contents of the published material are solely the responsibility of the authors and do not reflect the views of NHMRC.