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Title: Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.
Author: 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, Høgdall 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, García-Closas M, Brucker SY, Cybulski C, Harris HR, Hartkopf AD, Huzarski T, Jensen A, Lubiński J, Oszurek O, Benitez J, Mina F, Staebler A, Taran FA, Pasternak J, Talhouk A, Rossing MA, Hendley J, AOCS GroupPeter MacCallum Cancer Center, Melbourne, VIC, Australia.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Edwards RP, Fereday S, Modugno F, Ness RB, Sieh W, El-Bahrawy MA, Winham SJ, Lester J, Kjaer SK, Gronwald J, Sinn P, Fasching PA, Chang-Claude J, Moysich KB, Bowtell DD, Hernandez BY, Luk H, Behrens S, Shah M, Jung A, Ghatage P, Alsop J, Alsop K, García-Donas J, Thompson PJ, Swerdlow AJ, Karpinskyj C, Cazorla-Jiménez A, García MJ, Deen S, Wilkens LR, Palacios J, Berchuck A, Koziak JM, Brenton JD, Cook LS, Goode EL, Huntsman DG, Ramus SJ, Köbel M.
Journal: J Pathol Clin Res; 2018 Oct; 4(4):250-261. PubMed ID: 30062862.
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.

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