Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Filipe Correia Martins; Dominique Laurent Couturier; Anna Paterson; Anthony N. Karnezis; Christine Chow; Tayyebeh M. Nazeran; Adekunle Odunsi; Aleksandra Gentry-Maharaj; Aleksandra Vrvilo; Alexander Hein; Aline Talhouk; Ana Osorio; Andreas D. Hartkopf; Angela Brooks-Wilson; Anna DeFazio; Anna Fischer; Arndt Hartmann; Brenda Y. Hernandez; Bryan M. McCauley; Chloe Karpinskyj; Christiani B. de Sousa; Claus Høgdall; Daniel G. Tiezzi; Esther Herpel; Florin Andrei Taran; Francesmary Modugno; Gary Keeney; Gregg Nelson; Helen Steed; Honglin Song; Hugh Luk; Javier Benitez; Jennifer Alsop; Jennifer M. Koziak; Jenny Lester; Joseph H. Rothstein; Jurandyr M. de Andrade; Lene Lundvall; Luis Paz-Ares; Luis Robles-Díaz; Lynne R. Wilkens; Maria J. Garcia; Maria P. Intermaggio; Marie Lyne Alcaraz; Mary A. Brett; Matthias W. Beckmann; Mercedes Jimenez-Linan; Michael Anglesio; Michael E. Carney; Michael Schneider; Nadia Traficante; Nadja Pejovic; Naveena Singh; Nhu Le; Peter Sinn; Prafull Ghatage; Ramona Erber; Robert Edwards; Robert Vierkant; Roberta B. Ness; Samuel Leung; Sandra Orsulic; Sara Y. Brucker; Scott H. Kaufmann; Sian Fereday; Simon Gayther; Stacey J. Winham; Stefan Kommoss; Tanja Pejovic; Teri A. Longacre; Valerie McGuire; Valerie Rhenius; Weiva Sieh; Yurii B. Shvetsov; Alice S. Whittemore; Annette Staebler; Beth Y. Karlan; Cristina Rodriguez-Antona; David D. Bowtell; Ellen L. Goode; Estrid Høgdall; Francisco J. Candido dos Reis; Jacek Gronwald; Jenny Chang-Claude; Kirsten B. Moysich; Linda E. Kelemen; Linda S. Cook; Marc T. Goodman; Peter A. Fasching; Robin Crawford; Suha Deen; Usha Menon; David G. Huntsman; Martin Köbel; Susan J. Ramus; Paul D.P. Pharoah; James D. Brenton

doi:10.1038/s41416-020-0900-0

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Filipe Correia Martins, Dominique Laurent Couturier, Anna Paterson, Anthony N. Karnezis, Christine Chow, Tayyebeh M. Nazeran, Adekunle Odunsi, Aleksandra Gentry-Maharaj, Aleksandra Vrvilo, Alexander Hein, Aline Talhouk, Ana Osorio, Andreas D. Hartkopf, Angela Brooks-Wilson, Anna DeFazio, Anna Fischer, Arndt Hartmann, Brenda Y. Hernandez, Bryan M. McCauley, Chloe KarpinskyjChristiani B. de Sousa, Claus Høgdall, Daniel G. Tiezzi, Esther Herpel, Florin Andrei Taran, Francesmary Modugno, Gary Keeney, Gregg Nelson, Helen Steed, Honglin Song, Hugh Luk, Javier Benitez, Jennifer Alsop, Jennifer M. Koziak, Jenny Lester, Joseph H. Rothstein, Jurandyr M. de Andrade, Lene Lundvall, Luis Paz-Ares, Luis Robles-Díaz, Lynne R. Wilkens, Maria J. Garcia, Maria P. Intermaggio, Marie Lyne Alcaraz, Mary A. Brett, Matthias W. Beckmann, Mercedes Jimenez-Linan, Michael Anglesio, Michael E. Carney, Michael Schneider, Nadia Traficante, Nadja Pejovic, Naveena Singh, Nhu Le, Peter Sinn, Prafull Ghatage, Ramona Erber, Robert Edwards, Robert Vierkant, Roberta B. Ness, Samuel Leung, Sandra Orsulic, Sara Y. Brucker, Scott H. Kaufmann, Sian Fereday, Simon Gayther, Stacey J. Winham, Stefan Kommoss, Tanja Pejovic, Teri A. Longacre, Valerie McGuire, Valerie Rhenius, Weiva Sieh, Yurii B. Shvetsov, Alice S. Whittemore, Annette Staebler, Beth Y. Karlan, Cristina Rodriguez-Antona, David D. Bowtell, Ellen L. Goode, Estrid Høgdall, Francisco J. Candido dos Reis, Jacek Gronwald, Jenny Chang-Claude, Kirsten B. Moysich, Linda E. Kelemen, Linda S. Cook, Marc T. Goodman, Peter A. Fasching, Robin Crawford, Suha Deen, Usha Menon, David G. Huntsman, Martin Köbel, Susan J. Ramus, Paul D.P. Pharoah, James D. Brenton

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Original language	English
Pages (from-to)	793-802
Number of pages	10
Journal	British Journal of Cancer
Volume	123
Issue number	5
DOIs	https://doi.org/10.1038/s41416-020-0900-0
State	Published - 1 Sep 2020

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10.1038/s41416-020-0900-0

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Martins, F. C., Couturier, D. L., Paterson, A., Karnezis, A. N., Chow, C., Nazeran, T. M., Odunsi, A., Gentry-Maharaj, A., Vrvilo, A., Hein, A., Talhouk, A., Osorio, A., Hartkopf, A. D., Brooks-Wilson, A., DeFazio, A., Fischer, A., Hartmann, A., Hernandez, B. Y., McCauley, B. M., ... Brenton, J. D. (2020). Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium. British Journal of Cancer, 123(5), 793-802. https://doi.org/10.1038/s41416-020-0900-0

@article{ecf685295fb74a6d9e69b60293a83f22,

title = "Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium",

abstract = "Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.",

author = "Martins, {Filipe Correia} and Couturier, {Dominique Laurent} and Anna Paterson and Karnezis, {Anthony N.} and Christine Chow and Nazeran, {Tayyebeh M.} and Adekunle Odunsi and Aleksandra Gentry-Maharaj and Aleksandra Vrvilo and Alexander Hein and Aline Talhouk and Ana Osorio and Hartkopf, {Andreas D.} and Angela Brooks-Wilson and Anna DeFazio and Anna Fischer and Arndt Hartmann and Hernandez, {Brenda Y.} and McCauley, {Bryan M.} and Chloe Karpinskyj and {de Sousa}, {Christiani B.} and Claus H{\o}gdall and Tiezzi, {Daniel G.} and Esther Herpel and Taran, {Florin Andrei} and Francesmary Modugno and Gary Keeney and Gregg Nelson and Helen Steed and Honglin Song and Hugh Luk and Javier Benitez and Jennifer Alsop and Koziak, {Jennifer M.} and Jenny Lester and Rothstein, {Joseph H.} and {de Andrade}, {Jurandyr M.} and Lene Lundvall and Luis Paz-Ares and Luis Robles-D{\'i}az and Wilkens, {Lynne R.} and Garcia, {Maria J.} and Intermaggio, {Maria P.} and Alcaraz, {Marie Lyne} and Brett, {Mary A.} and Beckmann, {Matthias W.} and Mercedes Jimenez-Linan and Michael Anglesio and Carney, {Michael E.} and Michael Schneider and Nadia Traficante and Nadja Pejovic and Naveena Singh and Nhu Le and Peter Sinn and Prafull Ghatage and Ramona Erber and Robert Edwards and Robert Vierkant and Ness, {Roberta B.} and Samuel Leung and Sandra Orsulic and Brucker, {Sara Y.} and Kaufmann, {Scott H.} and Sian Fereday and Simon Gayther and Winham, {Stacey J.} and Stefan Kommoss and Tanja Pejovic and Longacre, {Teri A.} and Valerie McGuire and Valerie Rhenius and Weiva Sieh and Shvetsov, {Yurii B.} and Whittemore, {Alice S.} and Annette Staebler and Karlan, {Beth Y.} and Cristina Rodriguez-Antona and Bowtell, {David D.} and Goode, {Ellen L.} and Estrid H{\o}gdall and {Candido dos Reis}, {Francisco J.} and Jacek Gronwald and Jenny Chang-Claude and Moysich, {Kirsten B.} and Kelemen, {Linda E.} and Cook, {Linda S.} and Goodman, {Marc T.} and Fasching, {Peter A.} and Robin Crawford and Suha Deen and Usha Menon and Huntsman, {David G.} and Martin K{\"o}bel and Ramus, {Susan J.} and Pharoah, {Paul D.P.} and Brenton, {James D.}",

note = "Funding Information: Competing interests F.C.M. is a Clinical Lecturer for the Experimental Medicine Initiative from the University of Cambridge that is partly funded by AstraZeneca. A.P. was funded by NIHR (Academic Clinical Fellowship). A.D.F. has received a research grant from AstraZeneca, not directly to this work. D.D.B. receives funding from Astra Zeneca and Genentech Roche for the conduct of research studies and clinical trials unrelated to the work described in this article. D.G.H. is a founder and Chief Medical Officer of Contextual Genomics, a somatic mutation testing laboratory; the company{\textquoteright}s work and interests do not overlap with the subject of and methodologies used in this article. U.M. has stock ownership and has received research funding from Abcodia. No other disclosures are reported. P.D.P.P. is a member of the British Journal Cancer Editorial Board. All other authors declare no competing interests. Funding Information: Funding information F.C.M. is funded by the Experimental Medicine Initiative from the University of Cambridge, by the Academy of Medical Sciences (SGL016_1084), Cancer Research UK (C53876/A24267) and by the Addenbrooke{\textquoteright}s Charitable Trust (REF 13/17). Funding was provided by Canadian Institutes for Health Research (MOP-86727); Brazilian National Council for Scientific and Technological Development, grant No. 478416/2009-1; Calgary Laboratory Services Internal Research Competition RS10-533; German Federal Ministry of Education and Research of Germany (01 GB 9401); German Cancer Research Center (DKFZ); US National Cancer Institute K07-CA80668, P50-CA159981, R01CA095023; National Institutes of Health/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; US Army Medical Research and Materiel Command DAMD17-02-1-0669; NIH (R01-CA122443, P50-CA136393, P30-CA15083, U01-CA71966, U01-CA69417, R01-CA16056, K07-CA143047); Cancer Research UK (C490/A10119, C490/A10123, C490/A16561); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and at University College Hospital, {\textquoteleft}Women{\textquoteright}s Health Theme{\textquoteright}; NIH SFB 685; the Eve Appeal; the Oak Foundation and Deutsche Forschungsgemein-schaft. The Australian Ovarian Cancer Study Group was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729; The Cancer Council Victoria; Queensland Cancer Fund; The Cancer Council, New South Wales; the Tom Baker Cancer Centre Translational Laboratories; The Cancer Council, South Australia; The Cancer Foundation of Western Australia; The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The AOCS gratefully acknowledges additional support from the Peter MacCallum Cancer Foundation and Ovarian Cancer Australia (OCA). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling grants ID 310670 and ID 628903 and the Cancer Institute NSW grants 12/RIG/1-17 and 15/RIG/1-16. Funding for MALOVA was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, Maryland; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark and the Mermaid I project. A.D.F. is funded by Cancer Institute NSW grant 15/TRC/1-01. B.Y.K. is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124. The samples from the German Ovarian Cancer Study were provided by the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the ethics committee of Heidelberg University. F.J.C.d.R. is funded by the Brazilian National Council for Scientific and Technological Development – CNPq (427983/2016-9, 303210/2018-4). The UKOPS study was funded by The Eve Appeal (The Oak Foundation) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A.T. is funded through a Michael Smith Foundation for Health Research Scholar Award. M.A. is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars programme managed by the BC Cancer Foundation. D.G.H. receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs programme (Research Chair in Molecular and Genomic Pathology). OVCARE (including the VAN study) receives support through the BC Cancer Foundation and The VGH + UBC Hospital Foundation (relevant for authors A.T., D.G.H, S.L., C.C., A.N.K., and M.A.). J.D.B. acknowledges funding and support from Cancer Research UK (grant numbers A22905, A15601 and A17197). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = sep,

day = "1",

doi = "10.1038/s41416-020-0900-0",

language = "English",

volume = "123",

pages = "793--802",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "5",

}

Martins, FC, Couturier, DL, Paterson, A, Karnezis, AN, Chow, C, Nazeran, TM, Odunsi, A, Gentry-Maharaj, A, Vrvilo, A, Hein, A, Talhouk, A, Osorio, A, Hartkopf, AD, Brooks-Wilson, A, DeFazio, A, Fischer, A, Hartmann, A, Hernandez, BY, McCauley, BM, Karpinskyj, C, de Sousa, CB, Høgdall, C, Tiezzi, DG, Herpel, E, Taran, FA, Modugno, F, Keeney, G, Nelson, G, Steed, H, Song, H, Luk, H, Benitez, J, Alsop, J, Koziak, JM, Lester, J, Rothstein, JH, de Andrade, JM, Lundvall, L, Paz-Ares, L, Robles-Díaz, L, Wilkens, LR, Garcia, MJ, Intermaggio, MP, Alcaraz, ML, Brett, MA, Beckmann, MW, Jimenez-Linan, M, Anglesio, M, Carney, ME, Schneider, M, Traficante, N, Pejovic, N, Singh, N, Le, N, Sinn, P, Ghatage, P, Erber, R, Edwards, R, Vierkant, R, Ness, RB, Leung, S, Orsulic, S, Brucker, SY, Kaufmann, SH, Fereday, S, Gayther, S, Winham, SJ, Kommoss, S, Pejovic, T, Longacre, TA, McGuire, V, Rhenius, V, Sieh, W, Shvetsov, YB, Whittemore, AS, Staebler, A, Karlan, BY, Rodriguez-Antona, C, Bowtell, DD, Goode, EL, Høgdall, E, Candido dos Reis, FJ, Gronwald, J, Chang-Claude, J, Moysich, KB, Kelemen, LE, Cook, LS, Goodman, MT, Fasching, PA, Crawford, R, Deen, S, Menon, U, Huntsman, DG, Köbel, M, Ramus, SJ, Pharoah, PDP & Brenton, JD 2020, 'Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium', British Journal of Cancer, vol. 123, no. 5, pp. 793-802. https://doi.org/10.1038/s41416-020-0900-0

TY - JOUR

T1 - Clinical and pathological associations of PTEN expression in ovarian cancer

T2 - a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

AU - Martins, Filipe Correia

AU - Couturier, Dominique Laurent

AU - Paterson, Anna

AU - Karnezis, Anthony N.

AU - Chow, Christine

AU - Nazeran, Tayyebeh M.

AU - Odunsi, Adekunle

AU - Gentry-Maharaj, Aleksandra

AU - Vrvilo, Aleksandra

AU - Hein, Alexander

AU - Talhouk, Aline

AU - Osorio, Ana

AU - Hartkopf, Andreas D.

AU - Brooks-Wilson, Angela

AU - DeFazio, Anna

AU - Fischer, Anna

AU - Hartmann, Arndt

AU - Hernandez, Brenda Y.

AU - McCauley, Bryan M.

AU - Karpinskyj, Chloe

AU - de Sousa, Christiani B.

AU - Høgdall, Claus

AU - Tiezzi, Daniel G.

AU - Herpel, Esther

AU - Taran, Florin Andrei

AU - Modugno, Francesmary

AU - Keeney, Gary

AU - Nelson, Gregg

AU - Steed, Helen

AU - Song, Honglin

AU - Luk, Hugh

AU - Benitez, Javier

AU - Alsop, Jennifer

AU - Koziak, Jennifer M.

AU - Lester, Jenny

AU - Rothstein, Joseph H.

AU - de Andrade, Jurandyr M.

AU - Lundvall, Lene

AU - Paz-Ares, Luis

AU - Robles-Díaz, Luis

AU - Wilkens, Lynne R.

AU - Garcia, Maria J.

AU - Intermaggio, Maria P.

AU - Alcaraz, Marie Lyne

AU - Brett, Mary A.

AU - Beckmann, Matthias W.

AU - Jimenez-Linan, Mercedes

AU - Anglesio, Michael

AU - Carney, Michael E.

AU - Schneider, Michael

AU - Traficante, Nadia

AU - Pejovic, Nadja

AU - Singh, Naveena

AU - Le, Nhu

AU - Sinn, Peter

AU - Ghatage, Prafull

AU - Erber, Ramona

AU - Edwards, Robert

AU - Vierkant, Robert

AU - Ness, Roberta B.

AU - Leung, Samuel

AU - Orsulic, Sandra

AU - Brucker, Sara Y.

AU - Kaufmann, Scott H.

AU - Fereday, Sian

AU - Gayther, Simon

AU - Winham, Stacey J.

AU - Kommoss, Stefan

AU - Pejovic, Tanja

AU - Longacre, Teri A.

AU - McGuire, Valerie

AU - Rhenius, Valerie

AU - Sieh, Weiva

AU - Shvetsov, Yurii B.

AU - Whittemore, Alice S.

AU - Staebler, Annette

AU - Karlan, Beth Y.

AU - Rodriguez-Antona, Cristina

AU - Bowtell, David D.

AU - Goode, Ellen L.

AU - Høgdall, Estrid

AU - Candido dos Reis, Francisco J.

AU - Gronwald, Jacek

AU - Chang-Claude, Jenny

AU - Moysich, Kirsten B.

AU - Kelemen, Linda E.

AU - Cook, Linda S.

AU - Goodman, Marc T.

AU - Fasching, Peter A.

AU - Crawford, Robin

AU - Deen, Suha

AU - Menon, Usha

AU - Huntsman, David G.

AU - Köbel, Martin

AU - Ramus, Susan J.

AU - Pharoah, Paul D.P.

AU - Brenton, James D.

N1 - Funding Information: Competing interests F.C.M. is a Clinical Lecturer for the Experimental Medicine Initiative from the University of Cambridge that is partly funded by AstraZeneca. A.P. was funded by NIHR (Academic Clinical Fellowship). A.D.F. has received a research grant from AstraZeneca, not directly to this work. D.D.B. receives funding from Astra Zeneca and Genentech Roche for the conduct of research studies and clinical trials unrelated to the work described in this article. D.G.H. is a founder and Chief Medical Officer of Contextual Genomics, a somatic mutation testing laboratory; the company’s work and interests do not overlap with the subject of and methodologies used in this article. U.M. has stock ownership and has received research funding from Abcodia. No other disclosures are reported. P.D.P.P. is a member of the British Journal Cancer Editorial Board. All other authors declare no competing interests. Funding Information: Funding information F.C.M. is funded by the Experimental Medicine Initiative from the University of Cambridge, by the Academy of Medical Sciences (SGL016_1084), Cancer Research UK (C53876/A24267) and by the Addenbrooke’s Charitable Trust (REF 13/17). Funding was provided by Canadian Institutes for Health Research (MOP-86727); Brazilian National Council for Scientific and Technological Development, grant No. 478416/2009-1; Calgary Laboratory Services Internal Research Competition RS10-533; German Federal Ministry of Education and Research of Germany (01 GB 9401); German Cancer Research Center (DKFZ); US National Cancer Institute K07-CA80668, P50-CA159981, R01CA095023; National Institutes of Health/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; US Army Medical Research and Materiel Command DAMD17-02-1-0669; NIH (R01-CA122443, P50-CA136393, P30-CA15083, U01-CA71966, U01-CA69417, R01-CA16056, K07-CA143047); Cancer Research UK (C490/A10119, C490/A10123, C490/A16561); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and at University College Hospital, ‘Women’s Health Theme’; NIH SFB 685; the Eve Appeal; the Oak Foundation and Deutsche Forschungsgemein-schaft. The Australian Ovarian Cancer Study Group was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729; The Cancer Council Victoria; Queensland Cancer Fund; The Cancer Council, New South Wales; the Tom Baker Cancer Centre Translational Laboratories; The Cancer Council, South Australia; The Cancer Foundation of Western Australia; The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID400413, ID400281). The AOCS gratefully acknowledges additional support from the Peter MacCallum Cancer Foundation and Ovarian Cancer Australia (OCA). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling grants ID 310670 and ID 628903 and the Cancer Institute NSW grants 12/RIG/1-17 and 15/RIG/1-16. Funding for MALOVA was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, Maryland; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark and the Mermaid I project. A.D.F. is funded by Cancer Institute NSW grant 15/TRC/1-01. B.Y.K. is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124. The samples from the German Ovarian Cancer Study were provided by the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the ethics committee of Heidelberg University. F.J.C.d.R. is funded by the Brazilian National Council for Scientific and Technological Development – CNPq (427983/2016-9, 303210/2018-4). The UKOPS study was funded by The Eve Appeal (The Oak Foundation) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A.T. is funded through a Michael Smith Foundation for Health Research Scholar Award. M.A. is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars programme managed by the BC Cancer Foundation. D.G.H. receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology and the Canada Research Chairs programme (Research Chair in Molecular and Genomic Pathology). OVCARE (including the VAN study) receives support through the BC Cancer Foundation and The VGH + UBC Hospital Foundation (relevant for authors A.T., D.G.H, S.L., C.C., A.N.K., and M.A.). J.D.B. acknowledges funding and support from Cancer Research UK (grant numbers A22905, A15601 and A17197). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Publisher Copyright: © 2020, The Author(s).

PY - 2020/9/1

Y1 - 2020/9/1

N2 - Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

AB - Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

UR - http://www.scopus.com/inward/record.url?scp=85086506338&partnerID=8YFLogxK

U2 - 10.1038/s41416-020-0900-0

DO - 10.1038/s41416-020-0900-0

M3 - Article

C2 - 32555365

AN - SCOPUS:85086506338

SN - 0007-0920

VL - 123

SP - 793

EP - 802

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 5

ER -

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

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