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

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

doi:10.1002/cjp2.2018.4.issue-4

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

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

Department of Clinical Medicine

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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 language	English
Journal	The Journal of Pathology: Clinical Research
Volume	4
Issue number	4
Pages (from-to)	250-261
ISSN	2056-4538
DOIs	https://doi.org/10.1002/cjp2.2018.4.issue-4
Publication status	Published - 1 Oct 2018

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Rambau, P. F., Vierkant, R. A., Intermaggio, M. P., Kelemen, L. E., Goodman, M. T., Herpel, E., Pharoah, P. D., Kommoss, S., Jimenez-Linan, M., Karlan, B. Y., Gentry-Maharaj, A., Menon, U., Polo, S. H., Candido Dos Reis, F. J., Doherty, J. A., Gayther, S. A., Sharma, R., Larson, M. C., Harnett, P. R., ... Köbel, M. (2018). Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study. The Journal of Pathology: Clinical Research, 4(4), 250-261. https://doi.org/10.1002/cjp2.2018.4.issue-4

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes : an Ovarian Tumor Tissue Analysis consortium study. / Rambau, Peter F; Vierkant, Robert A; Intermaggio, Maria P et al.

In: The Journal of Pathology: Clinical Research, Vol. 4, No. 4, 01.10.2018, p. 250-261.

Research output: Contribution to journal › Journal article › Research › peer-review

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 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 2018, 'Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study', The Journal of Pathology: Clinical Research, vol. 4, no. 4, pp. 250-261. https://doi.org/10.1002/cjp2.2018.4.issue-4

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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.",

author = "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 Lubi{\'n}ski and Oleg Oszurek and Javier Benitez and Fady Mina and Annette Staebler and Taran, {Florin Andrei} and Jana Pasternak and Aline Talhouk and Rossing, {Mary Anne} and Joy Hendley and {AOCS Group} and Edwards, {Robert P} and Sian Fereday and Francesmary Modugno and Ness, {Roberta B} and Weiva Sieh and El-Bahrawy, {Mona A} and Winham, {Stacey J} and Jenny Lester and Kjaer, {Susanne K} and Jacek Gronwald and Peter Sinn and Fasching, {Peter A} and Jenny Chang-Claude and Moysich, {Kirsten B} and Bowtell, {David D} and Hernandez, {Brenda Y} and Hugh Luk and Sabine Behrens and Mitul Shah and Audrey Jung and Prafull Ghatage and Jennifer Alsop and Kathryn Alsop and Jes{\'u}s Garc{\'i}a-Donas and Thompson, {Pamela J} and Swerdlow, {Anthony J} and Chloe Karpinskyj and Alicia Cazorla-Jim{\'e}nez and Garc{\'i}a, {Mar{\'i}a J} and Susha Deen and Wilkens, {Lynne R} and Jos{\'e} Palacios and Andrew Berchuck and Koziak, {Jennifer M} and Brenton, {James D} and Cook, {Linda S} and Goode, {Ellen L} and Huntsman, {David G} and Ramus, {Susan J} and Martin K{\"o}bel",

year = "2018",

month = oct,

day = "1",

doi = "10.1002/cjp2.2018.4.issue-4",

language = "English",

volume = "4",

pages = "250--261",

journal = "The Journal of Pathology: Clinical Research",

issn = "2056-4538",

publisher = "JohnWiley & Sons Ltd",

number = "4",

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TY - JOUR

T1 - Association of p16 expression with prognosis varies across ovarian carcinoma histotypes

T2 - an Ovarian Tumor Tissue Analysis consortium study

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 - Mina, Fady

AU - Staebler, Annette

AU - Taran, Florin Andrei

AU - Pasternak, Jana

AU - Talhouk, Aline

AU - Rossing, Mary Anne

AU - Hendley, Joy

AU - AOCS Group

AU - Edwards, Robert P

AU - Fereday, Sian

AU - Modugno, Francesmary

AU - Ness, Roberta B

AU - Sieh, Weiva

AU - El-Bahrawy, Mona A

AU - Winham, Stacey J

AU - Lester, Jenny

AU - Kjaer, Susanne K

AU - Gronwald, Jacek

AU - Sinn, Peter

AU - Fasching, Peter A

AU - Chang-Claude, Jenny

AU - Moysich, Kirsten B

AU - Bowtell, David D

AU - Hernandez, Brenda Y

AU - Luk, Hugh

AU - Behrens, Sabine

AU - Shah, Mitul

AU - Jung, Audrey

AU - Ghatage, Prafull

AU - Alsop, Jennifer

AU - Alsop, Kathryn

AU - García-Donas, Jesús

AU - Thompson, Pamela J

AU - Swerdlow, Anthony J

AU - Karpinskyj, Chloe

AU - Cazorla-Jiménez, Alicia

AU - García, María J

AU - Deen, Susha

AU - Wilkens, Lynne R

AU - Palacios, José

AU - Berchuck, Andrew

AU - Koziak, Jennifer M

AU - Brenton, James D

AU - Cook, Linda S

AU - Goode, Ellen L

AU - Huntsman, David G

AU - Ramus, Susan J

AU - Köbel, Martin

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.

U2 - 10.1002/cjp2.2018.4.issue-4

DO - 10.1002/cjp2.2018.4.issue-4

M3 - Journal article

SN - 2056-4538

VL - 4

SP - 250

EP - 261

JO - The Journal of Pathology: Clinical Research

JF - The Journal of Pathology: Clinical Research

IS - 4

ER -

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

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