MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Australian Ovarian Cancer Study Group; Matthew S. Block; Robert A. Vierkant; Peter F. Rambau; Stacey J. Winham; Philipp Wagner; Nadia Traficante; Aleksandra Toloczko; 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 Lubinski; 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-Glaz; Georgia Chenevix-Trench; Alicia Cazorla; Sara Y. Brucker; David D. Bowtell; S. Brown; M. Links; J. Hill; B. Brown

doi:10.1016/j.mayocp.2017.10.023

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Australian Ovarian Cancer Study Group, Matthew S. Block, Robert A. Vierkant, Peter F. Rambau, Stacey J. Winham, Philipp Wagner, Nadia Traficante, Aleksandra Toloczko, 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 NelsonFrancesmary Modugno, Janusz Menkiszak, Valerie McGuire, Bryan M. McCauley, Marie Mack, Jan Lubinski, 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-Glaz, Georgia Chenevix-Trench, Alicia Cazorla, Sara Y. Brucker, David D. Bowtell, S. Brown, M. Links, J. Hill, B. Brown

Faculty of Health Sciences & Medicine

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

28 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	307-320
Number of pages	14
Journal	Mayo Clinic Proceedings
Volume	93
Issue number	3
DOIs	https://doi.org/10.1016/j.mayocp.2017.10.023
Publication status	Published - 1 Mar 2018

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MyD88 and TLR4 Expression in Epithelial Ovarian CancerFinal published version, 1.58 MBLicence: CC BY-NC-ND

Cite this

Australian Ovarian Cancer Study Group, Block, M. S., Vierkant, R. A., Rambau, P. F., Winham, S. J., Wagner, P., Traficante, N., Toloczko, A., Tiezzi, D. G., Taran, F. A., Sinn, P., Sieh, W., Sharma, R., Rothstein, J. H., Ramón y Cajal, T., Paz-Ares, L., Oszurek, O., Orsulic, S., Ness, R. B., ... Brown, B. (2018). MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. Mayo Clinic Proceedings, 93(3), 307-320. https://doi.org/10.1016/j.mayocp.2017.10.023

@article{1acaf47693824a7090a532c2737a7cca,

title = "MyD88 and TLR4 Expression in Epithelial Ovarian Cancer",

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.",

author = "{Australian Ovarian Cancer Study Group} and Block, {Matthew S.} and Vierkant, {Robert A.} and Rambau, {Peter F.} and Winham, {Stacey J.} and Philipp Wagner and Nadia Traficante and Aleksandra Toloczko and Tiezzi, {Daniel G.} and Taran, {Florin Andrei} and Peter Sinn and Weiva Sieh and Raghwa Sharma and Rothstein, {Joseph H.} and {Ram{\'o}n y Cajal}, Teresa and Luis Paz-Ares and Oleg Oszurek and Sandra Orsulic and Ness, {Roberta B.} and Gregg Nelson and Francesmary Modugno and Janusz Menkiszak and Valerie McGuire and McCauley, {Bryan M.} and Marie Mack and Jan Lubinski and Longacre, {Teri A.} and Zheng Li and Jenny Lester and Kennedy, {Catherine J.} and Kalli, {Kimberly R.} and Jung, {Audrey Y.} and Johnatty, {Sharon E.} and Mercedes Jimenez-Linan and Allan Jensen and Intermaggio, {Maria P.} and Jillian Hung and Esther Herpel and Hernandez, {Brenda Y.} and Hartkopf, {Andreas D.} and Harnett, {Paul R.} and Prafull Ghatage and Garc{\'i}a-Bueno, {Jos{\'e} M.} and Bo Gao and Sian Fereday and Ursula Eilber and Edwards, {Robert P.} and {de Sousa}, {Christiani B.} and {de Andrade}, {Jurandyr M.} and Anita Chudecka-Glaz and Georgia Chenevix-Trench and Alicia Cazorla and Brucker, {Sara Y.} and Bowtell, {David D.} and A. Green and P. Webb and {de Fazio}, Anna and D. Gertig and S. Moore and K. Harrap and T. Sadkowsky and N. Pandeya and M. Malt and A. Mellon and R. Robertson and {Vanden Bergh}, T. and M. Jones and P. Mackenzie and J. Maidens and K. Nattress and Chiew, {Y. E.} and A. Stenlake and H. Sullivan and B. Alexander and P. Ashover and S. Brown and T. Corrish and L. Green and L. Jackman and K. Ferguson and K. Martin and A. Martyn and B. Ranieri and J. White and V. Jayde and P. Mamers and L. Bowes and L. Galletta and D. Giles and J. Hendley and K. Alsop and T. Schmidt and H. Shirley and C. Ball and C. Young and S. Viduka and Hoa Tran and Sanela Bilic and Lydia Glavinas and Julia Brooks and R. Stuart-Harris and F. Kirsten and J. Rutovitz and P. Clingan and A. Glasgow and A. Proietto and S. Braye and G. Otton and J. Shannon and T. Bonaventura and J. Stewart and S. Begbie and M. Friedlander and D. Bell and S. Baron-Hay and A. Ferrier and G. Gard and D. Nevell and N. Pavlakis and S. Valmadre and B. Young and C. Camaris and R. Crouch and L. Edwards and N. Hacker and D. Marsden and G. Robertson and P. Beale and J. Beith and J. Carter and C. Dalrymple and R. Houghton and P. Russell and M. Links and J. Grygiel and J. Hill and A. Brand and K. Byth and R. Jaworski and G. Wain and B. Ward and D. Papadimos and A. Crandon and M. Cummings and K. Horwood and A. Obermair and L. Perrin and D. Wyld and J. Nicklin and M. Davy and Oehler, {M. K.} and C. Hall and T. Dodd and T. Healy and K. Pittman and D. Henderson and J. Miller and J. Pierdes and P. Blomfield and D. Challis and R. McIntosh and A. Parker and B. Brown and R. Rome and D. Allen and P. Grant and S. Hyde and R. Laurie and M. Robbie and D. Healy and T. Jobling and T. Manolitsas and J. McNealage and P. Rogers and B. Susil and E. Sumithran and I. Simpson and K. Phillips and D. Rischin and S. Fox and D. Johnson and S. Lade and M. Loughrey and N. O'Callaghan and W. Murray and P. Waring and V. Billson and J. Pyman and D. Neesham and M. Quinn and C. Underhill and R. Bell and Ng, {L. F.} and R. Blum and V. Ganju and I. Hammond and Y. Leung and A. McCartney and M. Buck and I. Haviv and D. Purdie and D. Whiteman and N. Zeps and Jennifer Alsop and Whittemore, {Alice S.} and Helen Steed and Annette Staebler and Moysich, {Kirsten B.} and Usha Menon and Koziak, {Jennifer M.} and Stefan Kommoss and Kjaer, {Susanne K.} and Kelemen, {Linda E.} and Karlan, {Beth Y.} and Huntsman, {David G.} and Estrid H{\o}gdall and Jacek Gronwald and Goodman, {Marc T.} and Blake Gilks and Garc{\'i}a, {Mar{\'i}a Jos{\'e}} and Fasching, {Peter A.} and Suha Deen and Jenny Chang-Claude and {Candido dos Reis}, {Francisco J.} and Campbell, {Ian G.} and Brenton, {James D.} and Javier Ben{\'i}tez and Pharoah, {Paul D.P.} and Martin K{\"o}bel and Ramus, {Susan J.} and Goode, {Ellen L.}",

note = "Funding Information: Grant Support: The work was supported by grant MOP-86727 from the Canadian Institutes for Health Research; grant 478416/2009-1 from the Brazilian National Council for Scientific and Technological Development; grant RS10-533 from the Calgary Laboratory Services Internal Research Competition; grant 01 GB 9401 from the German Federal Ministry of Education and Research of Germany; grants from the German Cancer Research Center (Deutsches Krebsforschungszentrum); grants K07-CA80668, P50-CA159981, and R01CA095023 from the US National Cancer Institute; grant MO1-RR000056 from the National Institutes of Health (NIH)/National Center for Research Resources/General Clinical Research Center; grant DAMD17-02-1-0669 from the US Army Medical Research and Materiel Command; grants R01-CA122443, P50-CA136393, P30-CA15083, U01-CA71966, U01-CA69417, R01-CA16056, and K07-CA143047 from the NIH; grants C490/A10119, C490/A10123, and C490/A16561 from Cancer Research UK; grants from the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and at University College Hospital “Womens Health Theme”; grant SFB 685 from the NIH; grants from the Eve Appeal; grants from the Oak Foundation; grants from Deutsche Forschungsgemein-schaft; grant DAMD17-01-1-0729 (A.O.C.S.) from the US Army Medical Research and Material Command; grants from the Cancer Council Victoria; grants from Queensland Cancer Fund; grants from the Cancer Council New South Wales; grants from the Cancer Council South Australia; grants from the Cancer Foundation of Western Australia; grants from the Cancer Council Tasmania; grants ID400413 and ID400281 from the National Health and Medical Research Council of Australia; grants from the Peter MacCallum Cancer Foundation and Ovarian Cancer Australia (A.O.C.S); enabling grants ID 310670 and ID 628903 (the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group) from the National Health and Medical Research Council; grants 12/RIG/1-17 and 15/RIG/1-16 from the Cancer Institute NSW (the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group); research grant R01- CA61107 (Malignant Ovarian Cancer Study) from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 (MALOVA) from the Danish Cancer Society, Copenhagen, Denmark, and a grant (Malignant Ovarian Cancer Study) from the Mermaid I project; grant 15/TRC/1-01 (A.F. and P.R.H.) from the Cancer Institute NSW; grant SIOP-06-258-01-COUN (B.Y.K.) from the American Cancer Society Early Detection Professorship; and grant UL1TR000124 from the National Center for Advancing Translational Sciences (B.Y.K.). Publisher Copyright: {\textcopyright} 2017 Mayo Foundation for Medical Education and Research",

year = "2018",

month = mar,

day = "1",

doi = "10.1016/j.mayocp.2017.10.023",

language = "English",

volume = "93",

pages = "307--320",

journal = "Mayo Clinic Proceedings",

issn = "0025-6196",

publisher = "Elsevier",

number = "3",

}

Australian Ovarian Cancer Study Group, Block, MS, Vierkant, RA, Rambau, PF, Winham, SJ, Wagner, P, Traficante, N, Toloczko, A, Tiezzi, DG, Taran, FA, Sinn, P, Sieh, W, Sharma, R, Rothstein, JH, Ramón y Cajal, T, Paz-Ares, L, Oszurek, O, Orsulic, S, Ness, RB, Nelson, G, Modugno, F, Menkiszak, J, McGuire, V, McCauley, BM, Mack, M, Lubinski, J, Longacre, TA, Li, Z, Lester, J, Kennedy, CJ, Kalli, KR, Jung, AY, Johnatty, SE, Jimenez-Linan, M, Jensen, A, Intermaggio, MP, Hung, J, Herpel, E, Hernandez, BY, Hartkopf, AD, Harnett, PR, Ghatage, P, García-Bueno, JM, Gao, B, Fereday, S, Eilber, U, Edwards, RP, de Sousa, CB, de Andrade, JM, Chudecka-Glaz, A, Chenevix-Trench, G, Cazorla, A, Brucker, SY, Bowtell, DD, Brown, S, Links, M, Hill, J & Brown, B 2018, 'MyD88 and TLR4 Expression in Epithelial Ovarian Cancer', Mayo Clinic Proceedings, vol. 93, no. 3, pp. 307-320. https://doi.org/10.1016/j.mayocp.2017.10.023

TY - JOUR

T1 - MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

AU - Australian Ovarian Cancer Study Group

AU - Block, Matthew S.

AU - Vierkant, Robert A.

AU - Rambau, Peter F.

AU - Winham, Stacey J.

AU - Wagner, Philipp

AU - Traficante, Nadia

AU - Toloczko, Aleksandra

AU - Tiezzi, Daniel G.

AU - Taran, Florin Andrei

AU - Sinn, Peter

AU - Sieh, Weiva

AU - Sharma, Raghwa

AU - Rothstein, Joseph H.

AU - Ramón y Cajal, Teresa

AU - Paz-Ares, Luis

AU - Oszurek, Oleg

AU - Orsulic, Sandra

AU - Ness, Roberta B.

AU - Nelson, Gregg

AU - Modugno, Francesmary

AU - Menkiszak, Janusz

AU - McGuire, Valerie

AU - McCauley, Bryan M.

AU - Mack, Marie

AU - Lubinski, Jan

AU - Longacre, Teri A.

AU - Li, Zheng

AU - Lester, Jenny

AU - Kennedy, Catherine J.

AU - Kalli, Kimberly R.

AU - Jung, Audrey Y.

AU - Johnatty, Sharon E.

AU - Jimenez-Linan, Mercedes

AU - Jensen, Allan

AU - Intermaggio, Maria P.

AU - Hung, Jillian

AU - Herpel, Esther

AU - Hernandez, Brenda Y.

AU - Hartkopf, Andreas D.

AU - Harnett, Paul R.

AU - Ghatage, Prafull

AU - García-Bueno, José M.

AU - Gao, Bo

AU - Fereday, Sian

AU - Eilber, Ursula

AU - Edwards, Robert P.

AU - de Sousa, Christiani B.

AU - de Andrade, Jurandyr M.

AU - Chudecka-Glaz, Anita

AU - Chenevix-Trench, Georgia

AU - Cazorla, Alicia

AU - Brucker, Sara Y.

AU - Bowtell, David D.

AU - Green, A.

AU - Webb, P.

AU - de Fazio, Anna

AU - Gertig, D.

AU - Moore, S.

AU - Harrap, K.

AU - Sadkowsky, T.

AU - Pandeya, N.

AU - Malt, M.

AU - Mellon, A.

AU - Robertson, R.

AU - Vanden Bergh, T.

AU - Jones, M.

AU - Mackenzie, P.

AU - Maidens, J.

AU - Nattress, K.

AU - Chiew, Y. E.

AU - Stenlake, A.

AU - Sullivan, H.

AU - Alexander, B.

AU - Ashover, P.

AU - Brown, S.

AU - Corrish, T.

AU - Green, L.

AU - Jackman, L.

AU - Ferguson, K.

AU - Martin, K.

AU - Martyn, A.

AU - Ranieri, B.

AU - White, J.

AU - Jayde, V.

AU - Mamers, P.

AU - Bowes, L.

AU - Galletta, L.

AU - Giles, D.

AU - Hendley, J.

AU - Alsop, K.

AU - Schmidt, T.

AU - Shirley, H.

AU - Ball, C.

AU - Young, C.

AU - Viduka, S.

AU - Tran, Hoa

AU - Bilic, Sanela

AU - Glavinas, Lydia

AU - Brooks, Julia

AU - Stuart-Harris, R.

AU - Kirsten, F.

AU - Rutovitz, J.

AU - Clingan, P.

AU - Glasgow, A.

AU - Proietto, A.

AU - Braye, S.

AU - Otton, G.

AU - Shannon, J.

AU - Bonaventura, T.

AU - Stewart, J.

AU - Begbie, S.

AU - Friedlander, M.

AU - Bell, D.

AU - Baron-Hay, S.

AU - Ferrier, A.

AU - Gard, G.

AU - Nevell, D.

AU - Pavlakis, N.

AU - Valmadre, S.

AU - Young, B.

AU - Camaris, C.

AU - Crouch, R.

AU - Edwards, L.

AU - Hacker, N.

AU - Marsden, D.

AU - Robertson, G.

AU - Beale, P.

AU - Beith, J.

AU - Carter, J.

AU - Dalrymple, C.

AU - Houghton, R.

AU - Russell, P.

AU - Links, M.

AU - Grygiel, J.

AU - Hill, J.

AU - Brand, A.

AU - Byth, K.

AU - Jaworski, R.

AU - Wain, G.

AU - Ward, B.

AU - Papadimos, D.

AU - Crandon, A.

AU - Cummings, M.

AU - Horwood, K.

AU - Obermair, A.

AU - Perrin, L.

AU - Wyld, D.

AU - Nicklin, J.

AU - Davy, M.

AU - Oehler, M. K.

AU - Hall, C.

AU - Dodd, T.

AU - Healy, T.

AU - Pittman, K.

AU - Henderson, D.

AU - Miller, J.

AU - Pierdes, J.

AU - Blomfield, P.

AU - Challis, D.

AU - McIntosh, R.

AU - Parker, A.

AU - Brown, B.

AU - Rome, R.

AU - Allen, D.

AU - Grant, P.

AU - Hyde, S.

AU - Laurie, R.

AU - Robbie, M.

AU - Healy, D.

AU - Jobling, T.

AU - Manolitsas, T.

AU - McNealage, J.

AU - Rogers, P.

AU - Susil, B.

AU - Sumithran, E.

AU - Simpson, I.

AU - Phillips, K.

AU - Rischin, D.

AU - Fox, S.

AU - Johnson, D.

AU - Lade, S.

AU - Loughrey, M.

AU - O'Callaghan, N.

AU - Murray, W.

AU - Waring, P.

AU - Billson, V.

AU - Pyman, J.

AU - Neesham, D.

AU - Quinn, M.

AU - Underhill, C.

AU - Bell, R.

AU - Ng, L. F.

AU - Blum, R.

AU - Ganju, V.

AU - Hammond, I.

AU - Leung, Y.

AU - McCartney, A.

AU - Buck, M.

AU - Haviv, I.

AU - Purdie, D.

AU - Whiteman, D.

AU - Zeps, N.

AU - Alsop, Jennifer

AU - Whittemore, Alice S.

AU - Steed, Helen

AU - Staebler, Annette

AU - Moysich, Kirsten B.

AU - Menon, Usha

AU - Koziak, Jennifer M.

AU - Kommoss, Stefan

AU - Kjaer, Susanne K.

AU - Kelemen, Linda E.

AU - Karlan, Beth Y.

AU - Huntsman, David G.

AU - Høgdall, Estrid

AU - Gronwald, Jacek

AU - Goodman, Marc T.

AU - Gilks, Blake

AU - García, María José

AU - Fasching, Peter A.

AU - Deen, Suha

AU - Chang-Claude, Jenny

AU - Candido dos Reis, Francisco J.

AU - Campbell, Ian G.

AU - Brenton, James D.

AU - Benítez, Javier

AU - Pharoah, Paul D.P.

AU - Köbel, Martin

AU - Ramus, Susan J.

AU - Goode, Ellen L.

N1 - Funding Information: Grant Support: The work was supported by grant MOP-86727 from the Canadian Institutes for Health Research; grant 478416/2009-1 from the Brazilian National Council for Scientific and Technological Development; grant RS10-533 from the Calgary Laboratory Services Internal Research Competition; grant 01 GB 9401 from the German Federal Ministry of Education and Research of Germany; grants from the German Cancer Research Center (Deutsches Krebsforschungszentrum); grants K07-CA80668, P50-CA159981, and R01CA095023 from the US National Cancer Institute; grant MO1-RR000056 from the National Institutes of Health (NIH)/National Center for Research Resources/General Clinical Research Center; grant DAMD17-02-1-0669 from the US Army Medical Research and Materiel Command; grants R01-CA122443, P50-CA136393, P30-CA15083, U01-CA71966, U01-CA69417, R01-CA16056, and K07-CA143047 from the NIH; grants C490/A10119, C490/A10123, and C490/A16561 from Cancer Research UK; grants from the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and at University College Hospital “Womens Health Theme”; grant SFB 685 from the NIH; grants from the Eve Appeal; grants from the Oak Foundation; grants from Deutsche Forschungsgemein-schaft; grant DAMD17-01-1-0729 (A.O.C.S.) from the US Army Medical Research and Material Command; grants from the Cancer Council Victoria; grants from Queensland Cancer Fund; grants from the Cancer Council New South Wales; grants from the Cancer Council South Australia; grants from the Cancer Foundation of Western Australia; grants from the Cancer Council Tasmania; grants ID400413 and ID400281 from the National Health and Medical Research Council of Australia; grants from the Peter MacCallum Cancer Foundation and Ovarian Cancer Australia (A.O.C.S); enabling grants ID 310670 and ID 628903 (the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group) from the National Health and Medical Research Council; grants 12/RIG/1-17 and 15/RIG/1-16 from the Cancer Institute NSW (the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group); research grant R01- CA61107 (Malignant Ovarian Cancer Study) from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 (MALOVA) from the Danish Cancer Society, Copenhagen, Denmark, and a grant (Malignant Ovarian Cancer Study) from the Mermaid I project; grant 15/TRC/1-01 (A.F. and P.R.H.) from the Cancer Institute NSW; grant SIOP-06-258-01-COUN (B.Y.K.) from the American Cancer Society Early Detection Professorship; and grant UL1TR000124 from the National Center for Advancing Translational Sciences (B.Y.K.). Publisher Copyright: © 2017 Mayo Foundation for Medical Education and Research

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85042274578&partnerID=8YFLogxK

U2 - 10.1016/j.mayocp.2017.10.023

DO - 10.1016/j.mayocp.2017.10.023

M3 - Article

C2 - 29502561

AN - SCOPUS:85042274578

SN - 0025-6196

VL - 93

SP - 307

EP - 320

JO - Mayo Clinic Proceedings

JF - Mayo Clinic Proceedings

IS - 3

ER -

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

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