Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study
Authors: Rambau Peter F , Vierkant Robert A , Intermaggio Maria P , Kelemen Linda E , Goodman Marc T , Herpel Esther , Pharoah Paul D , Kommoss Stefan , Jimenez‐Linan Mercedes , Karlan Beth Y , Gentry‐Maharaj Aleksandra , Menon Usha , Polo Susanna Hernando , Candido dos Reis Francisco J , Doherty Jennifer Anne , Gayther Simon A , Sharma Raghwa , Larson Melissa C , Harnett Paul R , Hatfield Emma , de Andrade Jurandyr M , Nelson Gregg S , Steed Helen , Schildkraut Joellen M , Carney Micheal E , Høgdall Estrid , Whittemore Alice S , Widschwendter Martin , Kennedy Catherine J , Wang Frances , Wang Qin , Wang Chen , Armasu Sebastian M , Daley Frances , Coulson Penny , Jones Micheal E , Anglesio Micheal S , Chow Christine , de Fazio Anna , García‐Closas Montserrat , Brucker Sara Y , Cybulski Cezary , Harris Holly R , Hartkopf Andreas D , Huzarski Tomasz , Jensen Allan , Lubiński Jan , Oszurek Oleg , Benitez Javier , Mina Fady , Staebler Annette , Taran Florin Andrei , Pasternak Jana , Talhouk Aline , Rossing Mary Anne , Hendley Joy ,   AOCS Group, Edwards Robert P , Fereday Sian , Modugno Francesmary , Ness Roberta B , Sieh Weiva , El‐Bahrawy Mona A , Winham Stacey J , Lester Jenny , Kjaer Susanne K , Gronwald Jacek , Sinn Peter , Fasching Peter A , Chang‐Claude Jenny , Moysich Kirsten B , Bowtell David D , Hernandez Brenda Y , Luk Hugh , Behrens Sabine , Shah Mitul , Jung Audrey , Ghatage Prafull , Alsop Jennifer , Alsop Kathryn , García‐Donas Jesús , Thompson Pamela J , Swerdlow Anthony J , Karpinskyj Chloe , Cazorla‐Jiménez Alicia , García María J , Deen Susha , Wilkens Lynne R , Palacios José , Berchuck Andrew , Koziak Jennifer M , Brenton James D , Cook Linda S , Goode Ellen L , Huntsman David G , Ramus Susan J , Köbel Martin 
Published: July 2018

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.