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^#^{1

2}, Tayyebeh M Nazeran^#², Sandra Lee³, Pauline Krämer^{1

4}, Evan S Cairns¹, Derek S Chiu², Samuel Cy Leung², Eun Young Kang³, Nicola S Meagher^{5

6}, Catherine J Kennedy^{7

8}, Jessica Boros^{7

8}, Friedrich Kommoss⁹, Hans-Walter Vollert¹⁰, Florian Heitz¹¹, Andreas du Bois¹¹, Philipp Harter¹¹, Marcel Grube^{1

4}, Bernhard Kraemer⁴, Annette Staebler¹², Felix Kf Kommoss¹³, Sabine Heublein¹⁴, Hans-Peter Sinn¹³, Naveena Singh¹⁵, Angela Laslavic¹⁶, Esther Elishaev¹⁷, Alex Olawaiye¹⁶, Kirsten Moysich¹⁸, Francesmary Modugno¹⁶, Raghwa Sharma^{19

20

21}, Alison H Brand^{8

20}, Paul R Harnett^{8

22}, Anna DeFazio^{7

8

20

23}, Renée T Fortner²⁴, Jan Lubinski²⁵, Marcin Lener²⁵, Aleksandra Tołoczko-Grabarek²⁵, Cezary Cybulski²⁵, Helena Gronwald²⁶, Jacek Gronwald²⁵, Penny Coulson²⁷, Mona A El-Bahrawy²⁸, Michael E Jones²⁷, Minouk J Schoemaker²⁷, Anthony J Swerdlow^{27

29}, Kylie L Gorringe^{30

31}, Ian Campbell^{30

32}, Linda Cook³³, Simon A Gayther³⁴, Michael E Carney³⁵, Yurii B Shvetsov³⁶, Brenda Y Hernandez³⁶, Lynne R Wilkens³⁶, Marc T Goodman³⁷, Constantina Mateoiu³⁸, Anna Linder³⁸, Karin Sundfeldt³⁸, Linda E Kelemen³⁹, Aleksandra Gentry-Maharaj^{40

41}, Martin Widschwendter⁴², Usha Menon⁴⁰, Kelly L Bolton⁴³, Jennifer Alsop⁴⁴, Mitul Shah⁴⁵, Mercedes Jimenez-Linan⁴⁵, Paul Dp Pharoah^{44

46}, James D Brenton⁴⁷, Kara L Cushing-Haugen⁴⁸, Holly R Harris⁴⁸, Jennifer A Doherty⁴⁹, Blake Gilks², Prafull Ghatage⁵⁰, David G Huntsman^{1

2}, Gregg S Nelson⁵⁰, Anna V Tinker^{2

51}, Cheng-Han Lee⁵², Ellen L Goode⁵³, Brad H Nelson⁵⁴, Susan J Ramus^{5

6}, Stefan Kommoss⁴, Aline Talhouk^{1

2}, Martin Köbel³, Michael S Anglesio^{1

2}

Affiliations

¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
² University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia's Gynecological Cancer Research Team (OVCARE), Vancouver, Canada.
³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada.
⁴ Department of Women's Health, University Hospital Tübingen, Tübingen, Germany.
⁵ University of New South Wales, Adult Cancer Program, Lowy Cancer Research Centre, Sydney, Australia.
⁶ University of New South Wales, School of Women's and Children's Health, Sydney, Australia.
⁷ The University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.
⁸ Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.
⁹ Medizin Campus Bodensee, Institute of Pathology, Friedrichshafen, Germany.
¹⁰ Department of Gynecology and Obstetrics, Medizin Campus Bodensee, Friedrichshafen, Germany.
¹¹ Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
¹² University Hospital Tübingen, Institute of Pathology and Neuropathology, Tübingen, Germany.
¹³ University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany.
¹⁴ Department of Obstetrics and Gynecology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.
¹⁵ Department of Pathology, Barts Health National Health Service Trust, London, UK.
¹⁶ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁷ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁸ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
¹⁹ Westmead Hospital, Tissue Pathology and Diagnostic Oncology, Sydney, Australia.
²⁰ University of Sydney, Sydney, Australia.
²¹ Western Sydney University, Sydney, Australia.
²² Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, Australia.
²³ The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, Australia.
²⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Department of Genetics and Pathology, International Hereditary Cancer Centre, Pomeranian Medical University, Szczecin, Poland.
²⁶ Department of Propaedeutics, Physical Diagnostics and Dental Physiotherapy, Pomeranian Medical University, Szczecin, Poland.
²⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁸ Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, UK.
²⁹ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
³⁰ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
³¹ Peter MacCallum Cancer Centre, Women's Cancer Program, Melbourne, Australia.
³² Peter MacCallum Cancer Centre, Cancer Genetics Laboratory, Research Division, Melbourne, Australia.
³³ Division of Epidemiology and Biostatistics, The University of New Mexico, Albuquerque, NM, USA.
³⁴ Cedars-Sinai Medical Center, Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Los Angeles, CA, USA.
³⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
³⁶ University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA.
³⁷ Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Los Angeles, CA, USA.
³⁸ Department of Obstetrics and Gynecology, Sahlgrenska Academy at Gothenburg University, Sahlgrenska Center for Cancer Research, Gothenburg, Sweden.
³⁹ Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁴⁰ University College London, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK.
⁴¹ University College London, Department of Women's Cancer, Institute for Women's Health, London, UK.
⁴² University of Innsbruck, EUTOPS Institute, Innsbruck, Austria.
⁴³ Department of Hematology and Oncology, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁵ Department of Histopathology, Addenbrookes Hospital, Cambridge, UK.
⁴⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁷ University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK.
⁴⁸ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁹ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁵⁰ Department of Oncology, Division of Gynecologic Oncology, University of Calgary, Calgary, Canada.
⁵¹ Department of Medicine, University of British Columbia, Vancouver, Canada.
⁵² University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton, Canada.
⁵³ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁵⁴ Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.

^# Contributed equally.

PMID: 34897700
PMCID: PMC9544180
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 et al. J Pathol. 2022 Apr.

. 2022 Apr;256(4):388-401.

doi: 10.1002/path.5849. Epub 2022 Feb 7.

Authors

Affiliations

¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
² University of British Columbia, Vancouver General Hospital, and BC Cancer. British Columbia's Gynecological Cancer Research Team (OVCARE), Vancouver, Canada.
³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Canada.
⁴ Department of Women's Health, University Hospital Tübingen, Tübingen, Germany.
⁵ University of New South Wales, Adult Cancer Program, Lowy Cancer Research Centre, Sydney, Australia.
⁶ University of New South Wales, School of Women's and Children's Health, Sydney, Australia.
⁷ The University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.
⁸ Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.
⁹ Medizin Campus Bodensee, Institute of Pathology, Friedrichshafen, Germany.
¹⁰ Department of Gynecology and Obstetrics, Medizin Campus Bodensee, Friedrichshafen, Germany.
¹¹ Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
¹² University Hospital Tübingen, Institute of Pathology and Neuropathology, Tübingen, Germany.
¹³ University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany.
¹⁴ Department of Obstetrics and Gynecology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.
¹⁵ Department of Pathology, Barts Health National Health Service Trust, London, UK.
¹⁶ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁷ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹⁸ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
¹⁹ Westmead Hospital, Tissue Pathology and Diagnostic Oncology, Sydney, Australia.
²⁰ University of Sydney, Sydney, Australia.
²¹ Western Sydney University, Sydney, Australia.
²² Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, Australia.
²³ The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, Australia.
²⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Department of Genetics and Pathology, International Hereditary Cancer Centre, Pomeranian Medical University, Szczecin, Poland.
²⁶ Department of Propaedeutics, Physical Diagnostics and Dental Physiotherapy, Pomeranian Medical University, Szczecin, Poland.
²⁷ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁸ Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, UK.
²⁹ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
³⁰ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
³¹ Peter MacCallum Cancer Centre, Women's Cancer Program, Melbourne, Australia.
³² Peter MacCallum Cancer Centre, Cancer Genetics Laboratory, Research Division, Melbourne, Australia.
³³ Division of Epidemiology and Biostatistics, The University of New Mexico, Albuquerque, NM, USA.
³⁴ Cedars-Sinai Medical Center, Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Los Angeles, CA, USA.
³⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
³⁶ University of Hawaii Cancer Center, Epidemiology Program, Honolulu, HI, USA.
³⁷ Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Los Angeles, CA, USA.
³⁸ Department of Obstetrics and Gynecology, Sahlgrenska Academy at Gothenburg University, Sahlgrenska Center for Cancer Research, Gothenburg, Sweden.
³⁹ Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
⁴⁰ University College London, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK.
⁴¹ University College London, Department of Women's Cancer, Institute for Women's Health, London, UK.
⁴² University of Innsbruck, EUTOPS Institute, Innsbruck, Austria.
⁴³ Department of Hematology and Oncology, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁵ Department of Histopathology, Addenbrookes Hospital, Cambridge, UK.
⁴⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁷ University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK.
⁴⁸ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁹ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁵⁰ Department of Oncology, Division of Gynecologic Oncology, University of Calgary, Calgary, Canada.
⁵¹ Department of Medicine, University of British Columbia, Vancouver, Canada.
⁵² University of Alberta, Department of Laboratory Medicine and Pathology, Edmonton, Canada.
⁵³ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁵⁴ Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.

^# Contributed equally.

PMID: 34897700
PMCID: PMC9544180
DOI: 10.1002/path.5849

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. © 2021 The Pathological Society of Great Britain and Ireland.

Keywords: ARID1A; CD8; DNA mismatch repair; clear cell ovarian carcinoma; endometrioid ovarian carcinoma; endometriosis-associated ovarian carcinoma; immunohistochemistry; prognosis.

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Figures

**Figure 1.**
Flowchart of case assignment for full and sub-cohort analysis including IHC staining images of ARID1A and epithelial CD8+ scoring in ENOC and CCOC each.

**Figure 2.**
Results from ARID1A classification in ovarian carcinomas. (A) Frequency of ARID1A loss detected in major ovarian carcinoma histological subtypes; ‘other’ contain cases of mixed cell, borderline and other specified epithelial ovarian tumours, (B,C) Oncoplot outlining full (B) ENOC and (C) CCOC cohort of cases (in columns) along with ARID1A, MMR and CD8+ status and clinicopathologic features. (D–F) Kaplan–Meier survival curves depicting OS (n=1044), DSS (n=936) and PFS (n=575) with absent vs. present ARID1A status in ENOC. (G–I) Kaplan–Meier survival curves depicting OS (n=538), DSS (n=437) and PFS (n=322) with absent versus present ARID1A status in CCO

See this image and copyright information in PMC

Comment in

Definitive study shows no association between ARID1A mutation status and clinical outcome in endometriosis-related ovarian cancers^‡.
Khalique S, Nash S, Natrajan R. Khalique S, et al. J Pathol. 2022 Sep;258(1):1-3. doi: 10.1002/path.5973. Epub 2022 Jun 29. J Pathol. 2022. PMID: 35647895 Free PMC article.

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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

Affiliations

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

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