Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

Karolin Heinze; Tayyebeh M. Nazeran; Sandra Lee; Pauline Krämer; Evan S. Cairns; Derek S. Chiu; Samuel C.Y. Leung; Eun Young Kang; Nicola S. Meagher; Catherine J. Kennedy; Jessica Boros; Friedrich Kommoss; Hans Walter Vollert; Florian Heitz; Andreas du Bois; Philipp Harter; Marcel Grube; Bernhard Kraemer; Annette Staebler; Felix K.F. Kommoss; Sabine Heublein; Hans Peter Sinn; Naveena Singh; Angela Laslavic; Esther Elishaev; Alex Olawaiye; Kirsten Moysich; Francesmary Modugno; Raghwa Sharma; Alison H. Brand; Paul R. Harnett; Anna DeFazio; Renée T. Fortner; Jan Lubinski; Marcin Lener; Aleksandra Tołoczko-Grabarek; Cezary Cybulski; Helena Gronwald; Jacek Gronwald; Penny Coulson; Mona A. El-Bahrawy; Michael E. Jones; Minouk J. Schoemaker; Anthony J. Swerdlow; Kylie L. Gorringe; Ian Campbell; Linda Cook; Simon A. Gayther; Michael E. Carney; Yurii B. Shvetsov; Brenda Y. Hernandez; Lynne R. Wilkens; Marc T. Goodman; Constantina Mateoiu; Anna Linder; Karin Sundfeldt; Linda E. Kelemen; Aleksandra Gentry-Maharaj; Martin Widschwendter; Usha Menon; Kelly L. Bolton; Jennifer Alsop; Mitul Shah; Mercedes Jimenez-Linan; Paul D.P. Pharoah; James D. Brenton; Kara L. Cushing-Haugen; Holly R. Harris; Jennifer A. Doherty; Blake Gilks; Prafull Ghatage; David G. Huntsman; Gregg S. Nelson; Anna V. Tinker; Cheng Han Lee; Ellen L. Goode; Brad H. Nelson; Susan J. Ramus; Stefan Kommoss; Aline Talhouk; Martin Köbel; Michael S. Anglesio

doi:10.1002/path.5849

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8⁺ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

Karolin Heinze, Tayyebeh M. Nazeran, Sandra Lee, Pauline Krämer, Evan S. Cairns, Derek S. Chiu, Samuel C.Y. Leung, Eun Young Kang, Nicola S. Meagher, Catherine J. Kennedy, Jessica Boros, Friedrich Kommoss, Hans Walter Vollert, Florian Heitz, Andreas du Bois, Philipp Harter, Marcel Grube, Bernhard Kraemer, Annette Staebler, Felix K.F. KommossSabine Heublein, Hans Peter Sinn, Naveena Singh, Angela Laslavic, Esther Elishaev, Alex Olawaiye, Kirsten Moysich, Francesmary Modugno, Raghwa Sharma, Alison H. Brand, Paul R. Harnett, Anna DeFazio, Renée T. Fortner, Jan Lubinski, Marcin Lener, Aleksandra Tołoczko-Grabarek, Cezary Cybulski, Helena Gronwald, Jacek Gronwald, Penny Coulson, Mona A. El-Bahrawy, Michael E. Jones, Minouk J. Schoemaker, Anthony J. Swerdlow, Kylie L. Gorringe, Ian Campbell, Linda Cook, Simon A. Gayther, Michael E. Carney, Yurii B. Shvetsov, Brenda Y. Hernandez, Lynne R. Wilkens, Marc T. Goodman, Constantina Mateoiu, Anna Linder, Karin Sundfeldt, Linda E. Kelemen, Aleksandra Gentry-Maharaj, Martin Widschwendter, Usha Menon, Kelly L. Bolton, Jennifer Alsop, Mitul Shah, Mercedes Jimenez-Linan, Paul D.P. Pharoah, James D. Brenton, Kara L. Cushing-Haugen, Holly R. Harris, Jennifer A. Doherty, Blake Gilks, Prafull Ghatage, David G. Huntsman, Gregg S. Nelson, Anna V. Tinker, Cheng Han Lee, Ellen L. Goode, Brad H. Nelson, Susan J. Ramus, Stefan Kommoss, Aline Talhouk, Martin Köbel, Michael S. Anglesio

Quantitative Health Sciences

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

Abstract

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8⁺ tumour-infiltrating lymphocytes (CD8⁺ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8⁺ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8⁺ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8⁺ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8⁺ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.

Original language	English (US)
Pages (from-to)	388-401
Number of pages	14
Journal	Journal of Pathology
Volume	256
Issue number	4
DOIs	https://doi.org/10.1002/path.5849
State	Published - Apr 2022

Keywords

ARID1A
CD8
DNA mismatch repair
clear cell ovarian carcinoma
endometrioid ovarian carcinoma
endometriosis-associated ovarian carcinoma
immunohistochemistry
prognosis

ASJC Scopus subject areas

Pathology and Forensic Medicine

Access to Document

10.1002/path.5849

Cite this

Heinze, K., Nazeran, T. M., Lee, S., Krämer, P., Cairns, E. S., Chiu, D. S., Leung, S. C. Y., Kang, E. Y., Meagher, N. S., Kennedy, C. J., Boros, J., Kommoss, F., Vollert, H. W., Heitz, F., du Bois, A., Harter, P., Grube, M., Kraemer, B., Staebler, A., ... Anglesio, M. S. (2022). Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8⁺ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas. Journal of Pathology, 256(4), 388-401. https://doi.org/10.1002/path.5849

Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8⁺ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas. / Heinze, Karolin; Nazeran, Tayyebeh M.; Lee, Sandra et al.

In: Journal of Pathology, Vol. 256, No. 4, 04.2022, p. 388-401.

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

Heinze, K, Nazeran, TM, Lee, S, Krämer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, HW, Heitz, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, HP, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Tołoczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, AV, Lee, CH, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Köbel, M & Anglesio, MS 2022, 'Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8⁺ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas', Journal of Pathology, vol. 256, no. 4, pp. 388-401. https://doi.org/10.1002/path.5849

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title = "Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas",

abstract = "ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.",

keywords = "ARID1A, CD8, DNA mismatch repair, clear cell ovarian carcinoma, endometrioid ovarian carcinoma, endometriosis-associated ovarian carcinoma, immunohistochemistry, prognosis",

author = "Karolin Heinze and Nazeran, {Tayyebeh M.} and Sandra Lee and Pauline Kr{\"a}mer and Cairns, {Evan S.} and Chiu, {Derek S.} and Leung, {Samuel C.Y.} and Kang, {Eun Young} and Meagher, {Nicola S.} and Kennedy, {Catherine J.} and Jessica Boros and Friedrich Kommoss and Vollert, {Hans Walter} and Florian Heitz and {du Bois}, Andreas and Philipp Harter and Marcel Grube and Bernhard Kraemer and Annette Staebler and Kommoss, {Felix K.F.} and Sabine Heublein and Sinn, {Hans Peter} and Naveena Singh and Angela Laslavic and Esther Elishaev and Alex Olawaiye and Kirsten Moysich and Francesmary Modugno and Raghwa Sharma and Brand, {Alison H.} and Harnett, {Paul R.} and Anna DeFazio and Fortner, {Ren{\'e}e T.} and Jan Lubinski and Marcin Lener and Aleksandra To{\l}oczko-Grabarek and Cezary Cybulski and Helena Gronwald and Jacek Gronwald and Penny Coulson and El-Bahrawy, {Mona A.} and Jones, {Michael E.} and Schoemaker, {Minouk J.} and Swerdlow, {Anthony J.} and Gorringe, {Kylie L.} and Ian Campbell and Linda Cook and Gayther, {Simon A.} and Carney, {Michael E.} and Shvetsov, {Yurii B.} and Hernandez, {Brenda Y.} and Wilkens, {Lynne R.} and Goodman, {Marc T.} and Constantina Mateoiu and Anna Linder and Karin Sundfeldt and Kelemen, {Linda E.} and Aleksandra Gentry-Maharaj and Martin Widschwendter and Usha Menon and Bolton, {Kelly L.} and Jennifer Alsop and Mitul Shah and Mercedes Jimenez-Linan and Pharoah, {Paul D.P.} and Brenton, {James D.} and Cushing-Haugen, {Kara L.} and Harris, {Holly R.} and Doherty, {Jennifer A.} and Blake Gilks and Prafull Ghatage and Huntsman, {David G.} and Nelson, {Gregg S.} and Tinker, {Anna V.} and Lee, {Cheng Han} and Goode, {Ellen L.} and Nelson, {Brad H.} and Ramus, {Susan J.} and Stefan Kommoss and Aline Talhouk and Martin K{\"o}bel and Anglesio, {Michael S.}",

note = "Funding Information: We thank all the study participants who contributed to this study and all the researchers, clinicians, and technical and administrative staff who have made this work possible. This research was funded in part by the Janet D. Cottrelle Foundation and the Canadian Institutes of Health Research (Early Career Investigator Grant to MS Anglesio). K Heinze is funded through a research scholarship by the Deutsche Forschungsgesellschaft (HE 8699/1-1). A Talhouk is funded through a Michael Smith Foundation for Health Research Scholar Award. M K{\"o}bel received support through the Calgary Laboratory Services research support fund (RS19-612). We thank Shuhong Liu and Young Ou (Anatomical Pathology Research Laboratory) for performing immunohistochemistry. MS Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. BC's Gynecological Cancer Research team (OVCARE) receives support through the BC Cancer Foundation and the VGH & UBC Hospital Foundation. This study uses resources provided by the Canadian Ovarian Cancer Research Consortium's COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l{\textquoteright}Universit{\'e} de Montr{\'e}al (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see https://www.tfri.ca/coeur). Ovarian tumour tissue analysis consortium studies were supported through independent mechanisms. The WMH study was supported by the Westmead Hospital Department of Gynaecological Oncology. 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 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. The Westmead GynBiobank acknowledges financial support from the Sydney West Translational Cancer Research Centre. The Sydney West Translational Cancer Research Centre is funded by the Cancer Institute NSW. The BGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. We thank the study staff, study participants, doctors, nurses, health care providers, and health information sources who have contributed to the study. The SWE study, KS, CM, AL, and the GynCancer Biobank in Western Sweden is financed by Swedish Cancer Foundation (KS), Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement (KS), and Assar Gabrielsson Foundation (CM, AL). The DOV study is funded by National Health Institute grants ID R01-CA168758, R01-CA112523, and R01-CA087538. The GER study was supported by the German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ), and thanks Sabine Behrens for competent technical assistance. The HAW study was funded by National Institutes of Health and National Cancer Institute Grants ID N01-CN-25403/CN, N01-CN-67001/CN, P30-CA-71789/CA, and R01-CA-58598/CA. The HOP study was supported by National Institutes of Health and National Cancer Institute Grants ID K07-CA80668, R01CA095023, and R01 CA126841, as well as by US Army Medical Research and Materiel Command DAMD17-02-1-0669 and NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056. MW is funded by the European Research Council Advanced Grant (H2020 BRCA-ERC under Grant Agreement No. 742432). The University of Cambridge has received salary support for author PDPP from the NHS in the East of England through the Clinical Academic Reserve. The SEA study (SEARCH) was supported through grants from Cancer Research UK (C490/A10119 C490/A10124 C490/A16561) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Publisher Copyright: {\textcopyright} 2021 The Pathological Society of Great Britain and Ireland.",

year = "2022",

month = apr,

doi = "10.1002/path.5849",

language = "English (US)",

volume = "256",

pages = "388--401",

journal = "Investigative and Cell Pathology",

issn = "0022-3417",

publisher = "John Wiley and Sons Ltd",

number = "4",

}

TY - JOUR

T1 - Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

AU - Heinze, Karolin

AU - Nazeran, Tayyebeh M.

AU - Lee, Sandra

AU - Krämer, Pauline

AU - Cairns, Evan S.

AU - Chiu, Derek S.

AU - Leung, Samuel C.Y.

AU - Kang, Eun Young

AU - Meagher, Nicola S.

AU - Kennedy, Catherine J.

AU - Boros, Jessica

AU - Kommoss, Friedrich

AU - Vollert, Hans Walter

AU - Heitz, Florian

AU - du Bois, Andreas

AU - Harter, Philipp

AU - Grube, Marcel

AU - Kraemer, Bernhard

AU - Staebler, Annette

AU - Kommoss, Felix K.F.

AU - Heublein, Sabine

AU - Sinn, Hans Peter

AU - Singh, Naveena

AU - Laslavic, Angela

AU - Elishaev, Esther

AU - Olawaiye, Alex

AU - Moysich, Kirsten

AU - Modugno, Francesmary

AU - Sharma, Raghwa

AU - Brand, Alison H.

AU - Harnett, Paul R.

AU - DeFazio, Anna

AU - Fortner, Renée T.

AU - Lubinski, Jan

AU - Lener, Marcin

AU - Tołoczko-Grabarek, Aleksandra

AU - Cybulski, Cezary

AU - Gronwald, Helena

AU - Gronwald, Jacek

AU - Coulson, Penny

AU - El-Bahrawy, Mona A.

AU - Jones, Michael E.

AU - Schoemaker, Minouk J.

AU - Swerdlow, Anthony J.

AU - Gorringe, Kylie L.

AU - Campbell, Ian

AU - Cook, Linda

AU - Gayther, Simon A.

AU - Carney, Michael E.

AU - Shvetsov, Yurii B.

AU - Hernandez, Brenda Y.

AU - Wilkens, Lynne R.

AU - Goodman, Marc T.

AU - Mateoiu, Constantina

AU - Linder, Anna

AU - Sundfeldt, Karin

AU - Kelemen, Linda E.

AU - Gentry-Maharaj, Aleksandra

AU - Widschwendter, Martin

AU - Menon, Usha

AU - Bolton, Kelly L.

AU - Alsop, Jennifer

AU - Shah, Mitul

AU - Jimenez-Linan, Mercedes

AU - Pharoah, Paul D.P.

AU - Brenton, James D.

AU - Cushing-Haugen, Kara L.

AU - Harris, Holly R.

AU - Doherty, Jennifer A.

AU - Gilks, Blake

AU - Ghatage, Prafull

AU - Huntsman, David G.

AU - Nelson, Gregg S.

AU - Tinker, Anna V.

AU - Lee, Cheng Han

AU - Goode, Ellen L.

AU - Nelson, Brad H.

AU - Ramus, Susan J.

AU - Kommoss, Stefan

AU - Talhouk, Aline

AU - Köbel, Martin

AU - Anglesio, Michael S.

N1 - Funding Information: We thank all the study participants who contributed to this study and all the researchers, clinicians, and technical and administrative staff who have made this work possible. This research was funded in part by the Janet D. Cottrelle Foundation and the Canadian Institutes of Health Research (Early Career Investigator Grant to MS Anglesio). K Heinze is funded through a research scholarship by the Deutsche Forschungsgesellschaft (HE 8699/1-1). A Talhouk is funded through a Michael Smith Foundation for Health Research Scholar Award. M Köbel received support through the Calgary Laboratory Services research support fund (RS19-612). We thank Shuhong Liu and Young Ou (Anatomical Pathology Research Laboratory) for performing immunohistochemistry. MS Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. BC's Gynecological Cancer Research team (OVCARE) receives support through the BC Cancer Foundation and the VGH & UBC Hospital Foundation. This study uses resources provided by the Canadian Ovarian Cancer Research Consortium's COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l’Université de Montréal (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see https://www.tfri.ca/coeur). Ovarian tumour tissue analysis consortium studies were supported through independent mechanisms. The WMH study was supported by the Westmead Hospital Department of Gynaecological Oncology. 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 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. The Westmead GynBiobank acknowledges financial support from the Sydney West Translational Cancer Research Centre. The Sydney West Translational Cancer Research Centre is funded by the Cancer Institute NSW. The BGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. We thank the study staff, study participants, doctors, nurses, health care providers, and health information sources who have contributed to the study. The SWE study, KS, CM, AL, and the GynCancer Biobank in Western Sweden is financed by Swedish Cancer Foundation (KS), Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement (KS), and Assar Gabrielsson Foundation (CM, AL). The DOV study is funded by National Health Institute grants ID R01-CA168758, R01-CA112523, and R01-CA087538. The GER study was supported by the German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ), and thanks Sabine Behrens for competent technical assistance. The HAW study was funded by National Institutes of Health and National Cancer Institute Grants ID N01-CN-25403/CN, N01-CN-67001/CN, P30-CA-71789/CA, and R01-CA-58598/CA. The HOP study was supported by National Institutes of Health and National Cancer Institute Grants ID K07-CA80668, R01CA095023, and R01 CA126841, as well as by US Army Medical Research and Materiel Command DAMD17-02-1-0669 and NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056. MW is funded by the European Research Council Advanced Grant (H2020 BRCA-ERC under Grant Agreement No. 742432). The University of Cambridge has received salary support for author PDPP from the NHS in the East of England through the Clinical Academic Reserve. The SEA study (SEARCH) was supported through grants from Cancer Research UK (C490/A10119 C490/A10124 C490/A16561) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. Publisher Copyright: © 2021 The Pathological Society of Great Britain and Ireland.

PY - 2022/4

Y1 - 2022/4

N2 - ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.

AB - ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012) and was associated with MMRd (p < 0.001) and the presence of CD8+ TILs (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8+ TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.

KW - ARID1A

KW - CD8

KW - DNA mismatch repair

KW - clear cell ovarian carcinoma

KW - endometrioid ovarian carcinoma

KW - endometriosis-associated ovarian carcinoma

KW - immunohistochemistry

KW - prognosis

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DO - 10.1002/path.5849

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