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

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: Peter F Rambau, Robert A Vierkant, Maria P Intermaggio, Linda E Kelemen, Marc T Goodman, Esther Herpel, Paul D Pharoah, Stefan Kommoss, Mercedes Jimenez-Linan, Beth Y Karlan, Aleksandra Gentry-Maharaj, Usha Menon, Susanna Hernando Polo, Francisco J Candido Dos Reis, Jennifer Anne Doherty, Simon A Gayther, Raghwa Sharma, Melissa C Larson, Paul R Harnett, Emma Hatfield, Jurandyr M de Andrade, Gregg S Nelson, Helen Steed, Joellen M Schildkraut, Micheal E Carney, Estrid Høgdall, Alice S Whittemore, Martin Widschwendter, Catherine J Kennedy, Frances Wang, Qin Wang, Chen Wang, Sebastian M Armasu, Frances Daley, Penny Coulson, Micheal E Jones, Micheal S Anglesio, Christine Chow, Anna de Fazio, Montserrat García-Closas, Sara Y Brucker, Cezary Cybulski, Holly R Harris, Andreas D Hartkopf, Tomasz Huzarski, Allan Jensen, Jan Lubiński, Oleg Oszurek, Javier Benitez, Fady Mina, Annette Staebler, Florin Andrei Taran, Jana Pasternak, Aline Talhouk, Mary Anne Rossing, Joy Hendley, AOCS Group, Robert P Edwards, Sian Fereday, Francesmary Modugno, Roberta B Ness, Weiva Sieh, Mona A El-Bahrawy, Stacey J Winham, Jenny Lester, Susanne K Kjaer, Jacek Gronwald, Peter Sinn, Peter A Fasching, Jenny Chang-Claude, Kirsten B Moysich, David D Bowtell, Brenda Y Hernandez, Hugh Luk, Sabine Behrens, Mitul Shah, Audrey Jung, Prafull Ghatage, Jennifer Alsop, Kathryn Alsop, Jesús García-Donas, Pamela J Thompson, Anthony J Swerdlow, Chloe Karpinskyj, Alicia Cazorla-Jiménez, María J García, Susha Deen, Lynne R Wilkens, José Palacios, Andrew Berchuck, Jennifer M Koziak, James D Brenton, Linda S Cook, Ellen L Goode, David G Huntsman, Susan J Ramus, Martin Köbel
• Journal: The journal of pathology. Clinical research (J Pathol Clin Res) Vol. 4 Issue 4 Pg. 250-261 (10 2018) ISSN: 2056-4538 [Electronic] England
• PMID: 30062862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.

Chemical References

• CDKN2A protein, human
• Cyclin-Dependent Kinase Inhibitor p16

Topics

• Adenocarcinoma, Mucinous (metabolism, mortality, pathology)
• Adult
• Aged
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Cystadenocarcinoma, Serous (metabolism, mortality, pathology)
• Female
• Humans
• Immunohistochemistry
• Middle Aged
• Ovarian Neoplasms (metabolism, mortality, pathology)
• Ovary (metabolism, pathology)
• Prognosis
• Survival Rate