MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Matthew S Block; Robert A Vierkant; Peter F Rambau; Stacey J Winham; Philipp Wagner; Nadia Traficante; Aleksandra Tołoczko; Daniel G Tiezzi; Florin Andrei Taran; Peter Sinn; Weiva Sieh; Raghwa Sharma; Joseph H Rothstein; Teresa Ramón Y Cajal; Luis Paz-Ares; Oleg Oszurek; Sandra Orsulic; Roberta B Ness; Gregg Nelson; Francesmary Modugno; Janusz Menkiszak; Valerie McGuire; Bryan M McCauley; Marie Mack; Jan Lubiński; Teri A Longacre; Zheng Li; Jenny Lester; Catherine J Kennedy; Kimberly R Kalli; Audrey Y Jung; Sharon E Johnatty; Mercedes Jimenez-Linan; Allan Jensen; Maria P Intermaggio; Jillian Hung; Esther Herpel; Brenda Y Hernandez; Andreas D Hartkopf; Paul R Harnett; Prafull Ghatage; José M García-Bueno; Bo Gao; Sian Fereday; Ursula Eilber; Robert P Edwards; Christiani B de Sousa; Jurandyr M de Andrade; Anita Chudecka-Głaz; Georgia Chenevix-Trench; Alicia Cazorla; Sara Y Brucker; Australian Ovarian Cancer Study Group; Jennifer Alsop; Alice S Whittemore; Helen Steed; Annette Staebler; Kirsten B Moysich; Usha Menon; Jennifer M Koziak; Stefan Kommoss; Susanne K Kjaer; Linda E Kelemen; Beth Y Karlan; David G Huntsman; Estrid Høgdall; Jacek Gronwald; Marc T Goodman; Blake Gilks; María José García; Peter A Fasching; Anna de Fazio; Suha Deen; Jenny Chang-Claude; Francisco J Candido Dos Reis; Ian G Campbell; James D Brenton; David D Bowtell; Javier Benítez; Paul D P Pharoah; Martin Köbel; Susan J Ramus; Ellen L Goode

doi:10.1016/j.mayocp.2017.10.023

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Mayo Clin Proc. 2018 Mar;93(3):307-320. doi: 10.1016/j.mayocp.2017.10.023.

Authors

Matthew S Block¹, Robert A Vierkant², Peter F Rambau³, Stacey J Winham², Philipp Wagner⁴, Nadia Traficante⁵, Aleksandra Tołoczko⁶, Daniel G Tiezzi⁷, Florin Andrei Taran⁴, Peter Sinn⁸, Weiva Sieh⁹, Raghwa Sharma¹⁰, Joseph H Rothstein⁹, Teresa Ramón Y Cajal¹¹, Luis Paz-Ares¹², Oleg Oszurek⁶, Sandra Orsulic¹³, Roberta B Ness¹⁴, Gregg Nelson¹⁵, Francesmary Modugno¹⁶, Janusz Menkiszak¹⁷, Valerie McGuire¹⁸, Bryan M McCauley², Marie Mack¹⁹, Jan Lubiński⁶, Teri A Longacre²⁰, Zheng Li²¹, Jenny Lester¹³, Catherine J Kennedy²², Kimberly R Kalli¹, Audrey Y Jung²³, Sharon E Johnatty²⁴, Mercedes Jimenez-Linan²⁵, Allan Jensen²⁶, Maria P Intermaggio²⁷, Jillian Hung²², Esther Herpel²⁸, Brenda Y Hernandez²⁹, Andreas D Hartkopf⁴, Paul R Harnett³⁰, Prafull Ghatage¹⁵, José M García-Bueno³¹, Bo Gao³⁰, Sian Fereday³², Ursula Eilber²³, Robert P Edwards³³, Christiani B de Sousa⁷, Jurandyr M de Andrade⁷, Anita Chudecka-Głaz¹⁷, Georgia Chenevix-Trench²⁴, Alicia Cazorla³⁴, Sara Y Brucker⁴; Australian Ovarian Cancer Study Group; Jennifer Alsop¹⁹, Alice S Whittemore³⁵, Helen Steed³⁶, Annette Staebler³⁷, Kirsten B Moysich³⁸, Usha Menon³⁹, Jennifer M Koziak⁴⁰, Stefan Kommoss⁴, Susanne K Kjaer⁴¹, Linda E Kelemen⁴², Beth Y Karlan¹³, David G Huntsman⁴³, Estrid Høgdall⁴⁴, Jacek Gronwald⁶, Marc T Goodman⁴⁵, Blake Gilks⁴⁶, María José García⁴⁷, Peter A Fasching⁴⁸, Anna de Fazio²², Suha Deen⁴⁹, Jenny Chang-Claude⁵⁰, Francisco J Candido Dos Reis⁷, Ian G Campbell⁵¹, James D Brenton⁵², David D Bowtell⁵³, Javier Benítez⁴⁷, Paul D P Pharoah⁵⁴, Martin Köbel⁵⁵, Susan J Ramus⁵⁶, Ellen L Goode⁵⁷

Collaborators

Australian Ovarian Cancer Study Group:
D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, A Mellon, R Robertson, T Vanden Bergh, M Jones, P Mackenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, P Mamers, L Bowes, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie, M Friedlander, D Bell, S Baron-Hay, A Ferrier, G Gard, D Nevell, N Pavlakis, S Valmadre, B Young, C Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson, P Beale, J Beith, J Carter, C Dalrymple, R Houghton, P Russell, M Links, J Grygiel, J Hill, A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain, B Ward, D Papadimos, A Crandon, M Cummings, K Horwood, A Obermair, L Perrin, D Wyld, J Nicklin, M Davy, M K Oehler, C Hall, T Dodd, T Healy, K Pittman, D Henderson, J Miller, J Pierdes, P Blomfield, D Challis, R McIntosh, A Parker, B Brown, R Rome, D Allen, P Grant, S Hyde, R Laurie, M Robbie, D Healy, T Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, K Phillips, D Rischin, S Fox, D Johnson, S Lade, M Loughrey, N O'Callaghan, W Murray, P Waring, V Billson, J Pyman, D Neesham, M Quinn, C Underhill, R Bell, L F Ng, R Blum, V Ganju, I Hammond, Y Leung, A McCartney, M Buck, I Haviv, D Purdie, D Whiteman, N Zeps

Affiliations

¹ Department of Medical Oncology, Mayo Clinic, Rochester, MN.
² Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania.
⁴ Tübingen University Hospital, Department of Women's Health, Tübingen, Germany.
⁵ Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia.
⁶ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁷ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁸ Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁹ Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁰ Pathology West ICPMR Westmead, Westmead Hospital, the University of Sydney, Sydney, Australia; University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
¹¹ Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
¹² H12O-CNIO Lung Cancer Clinical Research Unit, Madrid, Spain; Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
¹³ Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁴ University of Texas School of Public Health, Houston.
¹⁵ Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁶ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA.
¹⁷ Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
¹⁸ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA.
¹⁹ Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
²⁰ Department of Pathology, Stanford University, Stanford, CA.
²¹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN; Department of Gynecologic Oncology, the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China.
²² Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁴ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²⁵ Department of Histopathology, Addenbrookes Hospital, Cambridge, UK.
²⁶ Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
²⁷ School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
²⁸ Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
²⁹ Cancer Center, University of Hawaii, Honolulu, HI.
³⁰ Centre for Cancer Research, the Westmead Institute for Medical Research, the University of Sydney, Sydney, New South Wales, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, the University of Sydney, Sydney, Australia.
³¹ Oncology Department, Hospital General de Albacete, Madrid, Spain.
³² Department of Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
³³ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
³⁴ Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
³⁵ Department of Health Research and Policy and Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA.
³⁶ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada.
³⁷ Tübingen University Hospital, Institute of Pathology, Tübingen, Germany.
³⁸ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.
³⁹ Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
⁴⁰ Alberta Health Services-Cancer Care, Calgary, Alberta, Canada.
⁴¹ Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁴² Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC.
⁴³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
⁴⁴ Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
⁴⁶ Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
⁴⁷ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁴⁸ David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany.
⁴⁹ Department of Histopathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵⁰ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵¹ Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
⁵² Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK; Cambridge Experimental Cancer Medicine Centre, Cambridge, UK.
⁵³ Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia; Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Garvan Institute, Sydney, New South Wales, Australia.
⁵⁴ Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
⁵⁵ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
⁵⁶ School of Women's and Children's Health, University of New South Wales, Sydney, Australia; Garvan Institute, Sydney, New South Wales, Australia.
⁵⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN. Electronic address: [email protected].

Abstract

Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.

Patients and methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).

Results: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).

Conclusion: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Biomarkers, Tumor / metabolism
Carcinoma, Ovarian Epithelial / metabolism*
Carcinoma, Ovarian Epithelial / mortality
Female
Humans
Immunohistochemistry / methods
Middle Aged
Myeloid Differentiation Factor 88 / metabolism*
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / mortality
Survival Analysis
Tissue Array Analysis / methods
Toll-Like Receptor 4 / metabolism*

Substances

Biomarkers, Tumor
MYD88 protein, human
Myeloid Differentiation Factor 88
TLR4 protein, human
Toll-Like Receptor 4

Abstract

Publication types

MeSH terms

Substances

Grants and funding