TY - JOUR
T1 - Association of p16 expression with prognosis varies across ovarian carcinoma histotypes
T2 - an Ovarian Tumor Tissue Analysis consortium study
AU - AOCS Group
AU - Rambau, Peter F.
AU - Vierkant, Robert A.
AU - Intermaggio, Maria P.
AU - Kelemen, Linda E.
AU - Goodman, Marc T.
AU - Herpel, Esther
AU - Pharoah, Paul D.
AU - Kommoss, Stefan
AU - Jimenez-Linan, Mercedes
AU - Karlan, Beth Y.
AU - Gentry-Maharaj, Aleksandra
AU - Menon, Usha
AU - Polo, Susanna Hernando
AU - Candido Dos Reis, Francisco J.
AU - Doherty, Jennifer Anne
AU - Gayther, Simon A.
AU - Sharma, Raghwa
AU - Larson, Melissa C.
AU - Harnett, Paul R.
AU - Hatfield, Emma
AU - de Andrade, Jurandyr M.
AU - Nelson, Gregg S.
AU - Steed, Helen
AU - Schildkraut, Joellen M.
AU - Carney, Micheal E.
AU - Høgdall, Estrid
AU - Whittemore, Alice S.
AU - Widschwendter, Martin
AU - Kennedy, Catherine J.
AU - Wang, Frances
AU - Wang, Qin
AU - Wang, Chen
AU - Armasu, Sebastian M.
AU - Daley, Frances
AU - Coulson, Penny
AU - Jones, Micheal E.
AU - Anglesio, Micheal S.
AU - Chow, Christine
AU - de Fazio, Anna
AU - García-Closas, Montserrat
AU - Brucker, Sara Y.
AU - Cybulski, Cezary
AU - Harris, Holly R.
AU - Hartkopf, Andreas D.
AU - Huzarski, Tomasz
AU - Jensen, Allan
AU - Lubiński, Jan
AU - Oszurek, Oleg
AU - Benitez, Javier
AU - Sieh, Weiva
N1 - Publisher 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.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
KW - RT-QPCR
KW - immunocytochemistry
KW - ovary
UR - http://www.scopus.com/inward/record.url?scp=85054469059&partnerID=8YFLogxK
U2 - 10.1002/cjp2.109
DO - 10.1002/cjp2.109
M3 - Article
C2 - 30062862
AN - SCOPUS:85054469059
SN - 2056-4538
VL - 4
SP - 250
EP - 261
JO - Journal of Pathology: Clinical Research
JF - Journal of Pathology: Clinical Research
IS - 4
ER -