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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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; LubiƄski, J; Oszurek, O; Benitez, J; Mina, F; Staebler, A; Taran, FA; Pasternak, J; Talhouk, A; Rossing, MA; Hendley, J; AOCS Group, ; 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

Published Date

  • October 2018

Published In

Volume / Issue

  • 4 / 4

Start / End Page

  • 250 - 261

PubMed ID

  • 30062862

Pubmed Central ID

  • 30062862

Electronic International Standard Serial Number (EISSN)

  • 2056-4538

International Standard Serial Number (ISSN)

  • 2056-4538

Digital Object Identifier (DOI)

  • 10.1002/cjp2.109

Language

  • eng