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

Rambau PF, Vierkant RA, Intermaggio MP, Kelemen LE, Goodman MT, Herpel E, Pharoah PD, Kommoss S, Jimenez-Linan M, Karlan BY, Gentry-Maharaj A, Menon U, Polo SH, Candido Dos Reis FJ, Doherty JA, Gayther SA, Sharma R, Larson MC, Harnett PR, Hatfield E, De Andrade JM, Nelson GS, Steed H, Schildkraut JM, Carney ME, Hogdall E, Whittemore AS, Widschwendter M, Kennedy CJ, Wang F, Wang Q, Wang C, Armasu SM, Daley F, Coulson P, Jones ME, Anglesio MS, Chow C, De Fazio A, Garcia-Closas M, Brucker SY, Cybulski C, Harris HR, Hartkopf AD, Huzarski T, Jensen A, Lubinski J, Oszurek O, Benitez J, Mina F, Staebler A, Taran FA, Pasternak J, Talhouk A, Rossing MA, Hendley J, Edwards RP, Fereday S, Modugno F, Ness RB, Sieh W, El-Bahrawy MA, Winham SJ, Lester J, Kjaer SK, Gronwald J, Sinn P, Fasching P, Chang-Claude J, Moysich KB, Bowtell DD, Hernandez BY, Luk H, Behrens S, Shah M, Jung A, Ghatage P, Alsop J, Alsop K, Garcia-Donas J, Thompson PJ, Swerdlow AJ, Karpinskyj C, Cazorla-Jimenez A, Garcia MJ, Deen S, Wilkens LR, Palacios J, Berchuck A, Koziak JM, Brenton JD, Cook LS, Goode EL, Huntsman DG, Ramus SJ, Koebel M (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 4

Pages Range: 250-261

Journal Issue: 4

DOI: 10.1002/cjp2.109

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.

Authors with CRIS profile

Involved external institutions

University of New South Wales (UNSW) Australia (AU) University of Calgary Canada (CA) University of Sydney (USYD) Australia (AU) University of Southern California (USC) United States (USA) (US) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) Mayo Clinic United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Stanford University United States (USA) (US) Addenbrooke's Hospital United Kingdom (GB) Danish Cancer Society Research Center Denmark (DK) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Roswell Park Cancer Institute United States (USA) (US) The Institute of Cancer Research (ICR) United Kingdom (GB) University of Cambridge United Kingdom (GB) Universidad de Alcalá (UAH) Spain (ES) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Universitätsklinikum Tübingen Germany (DE) Fred Hutchinson Cancer Research Center Canada (CA) Universitätsklinikum Heidelberg Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Texas MD Anderson Cancer Center United States (USA) (US) Alberta Health Services (AHS) Canada (CA) University of British Columbia Canada (CA) University of Pittsburgh United States (USA) (US) Peter MacCallum Cancer Centre Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Duke University United States (USA) (US) University College London (UCL) United Kingdom (GB) Eberhard Karls Universität Tübingen Germany (DE) Icahn School of Medicine at Mount Sinai United States (USA) (US) Nottingham University Hospitals United Kingdom (GB) University of Virginia (UVA) United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Quirónsalud Spain (ES) HM Hospitales Spain (ES) University of Utah United States (USA) (US) Brunel University London United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Medical University of South Carolina (MUSC) United States (USA) (US) Hospital Universitario Fundación Alcorcón (HUFA) Spain (ES) Royal Alexandra Hospital (RAH) Canada (CA) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US)

How to cite

APA:

Rambau, P.F., Vierkant, R.A., Intermaggio, M.P., Kelemen, L.E., Goodman, M.T., Herpel, E.,... Koebel, M. (2018). Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study. Journal of Pathology: Clinical Research, 4(4), 250-261. https://doi.org/10.1002/cjp2.109

MLA:

Rambau, Peter F., et al. "Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study." Journal of Pathology: Clinical Research 4.4 (2018): 250-261.

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