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

AOCS Group

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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.

Original languageEnglish (US)
Pages (from-to)250-261
Number of pages12
JournalThe journal of pathology. Clinical research
Volume4
Issue number4
DOIs
StatePublished - Oct 1 2018

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Carcinoma
Neoplasms
Endometrioid Carcinoma
Mucinous Adenocarcinoma
Messenger RNA
Endometriosis
Proteins
Immunohistochemistry

Keywords

  • immunocytochemistry
  • ovary
  • RT-QPCR

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

@article{aeda1911c38647a6a74ed15375d0a2dc,
title = "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.",
keywords = "immunocytochemistry, ovary, RT-QPCR",
author = "{AOCS Group} and Rambau, {Peter F.} and Vierkant, {Robert A.} and Intermaggio, {Maria P.} and Kelemen, {Linda E.} and Goodman, {Marc T.} and Esther Herpel and Pharoah, {Paul D.} and Stefan Kommoss and Mercedes Jimenez-Linan and Karlan, {Beth Y.} and Aleksandra Gentry-Maharaj and Usha Menon and Polo, {Susanna Hernando} and {Candido Dos Reis}, {Francisco J.} and Doherty, {Jennifer Anne} and Gayther, {Simon A.} and Raghwa Sharma and Larson, {Melissa C.} and Harnett, {Paul R.} and Emma Hatfield and {de Andrade}, {Jurandyr M.} and Nelson, {Gregg S.} and Helen Steed and Schildkraut, {Joellen M.} and Carney, {Micheal E.} and Estrid H{\o}gdall and Whittemore, {Alice S.} and Martin Widschwendter and Kennedy, {Catherine J.} and Frances Wang and Qin Wang and Chen Wang and Armasu, {Sebastian M.} and Frances Daley and Penny Coulson and Jones, {Micheal E.} and Anglesio, {Micheal S.} and Christine Chow and {de Fazio}, Anna and Montserrat Garc{\'i}a-Closas and Brucker, {Sara Y.} and Cezary Cybulski and Harris, {Holly R.} and Hartkopf, {Andreas D.} and Tomasz Huzarski and Allan Jensen and Jan Lubiński and Oleg Oszurek and Winham, {Stacey J} and Goode, {Ellen L}",
year = "2018",
month = "10",
day = "1",
doi = "10.1002/cjp2.109",
language = "English (US)",
volume = "4",
pages = "250--261",
journal = "Journal of Pathology: Clinical Research",
issn = "2056-4538",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "4",

}

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 - Winham, Stacey J

AU - Goode, Ellen L

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 - immunocytochemistry

KW - ovary

KW - RT-QPCR

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U2 - 10.1002/cjp2.109

DO - 10.1002/cjp2.109

M3 - Article

C2 - 30062862

AN - SCOPUS:85054469059

VL - 4

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EP - 261

JO - Journal of Pathology: Clinical Research

JF - Journal of Pathology: Clinical Research

SN - 2056-4538

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