Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses

Eun Young Kang; Dane Cheasley; Cecile LePage; Matthew J. Wakefield; Michelle da Cunha Torres; Simone Rowley; Carolina Salazar; Zhongyue Xing; Prue E. Allan; David D.L. Bowtell; Anne Marie Mes-Masson; Diane M. Provencher; Kurosh Rahimi; Linda E. Kelemen; Peter A. Fasching; Jennifer A. Doherty; Marc T. Goodman; Ellen L. Goode; Suha Deen; Paul D.P. Pharoah; James D. Brenton; Weiva Sieh; Constantina Mateoiu; Karin Sundfeldt; Linda S. Cook; Nhu D. Le; Michael S. Anglesio; C. Blake Gilks; David G. Huntsman; Catherine J. Kennedy; Nadia Traficante; Anna DeFazio; Scott H. Kaufmann; Michael Churchman; Charlie Gourley; Andrew N. Stephens; Nicola S. Meagher; Susan J. Ramus; Yoland C. Antill; Ian Campbell; Clare L. Scott; Martin Köbel; Kylie L. Gorringe; Australian Ovarian Cancer Study Group (AOCS); GAMuT Collaborators

doi:10.1038/s41379-020-0618-9

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses

Eun Young Kang, Dane Cheasley, Cecile LePage, Matthew J. Wakefield, Michelle da Cunha Torres, Simone Rowley, Carolina Salazar, Zhongyue Xing, Prue E. Allan, David D.L. Bowtell, Anne Marie Mes-Masson, Diane M. Provencher, Kurosh Rahimi, Linda E. Kelemen, Peter A. Fasching, Jennifer A. Doherty, Marc T. Goodman, Ellen L. Goode, Suha Deen, Paul D.P. PharoahJames D. Brenton, Weiva Sieh, Constantina Mateoiu, Karin Sundfeldt, Linda S. Cook, Nhu D. Le, Michael S. Anglesio, C. Blake Gilks, David G. Huntsman, Catherine J. Kennedy, Nadia Traficante, Anna DeFazio, Scott H. Kaufmann, Michael Churchman, Charlie Gourley, Andrew N. Stephens, Nicola S. Meagher, Susan J. Ramus, Yoland C. Antill, Ian Campbell, Clare L. Scott, Martin Köbel, Kylie L. Gorringe, Australian Ovarian Cancer Study Group (AOCS), GAMuT Collaborators

Medicine Alfred Hospital

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

1 Citation (Scopus)

Abstract

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Original language	English
Pages (from-to)	194-206
Number of pages	13
Journal	Modern Pathology
Volume	34
Issue number	1
DOIs	https://doi.org/10.1038/s41379-020-0618-9
Publication status	Published - Jan 2021

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10.1038/s41379-020-0618-9

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Kang, E. Y., Cheasley, D., LePage, C., Wakefield, M. J., da Cunha Torres, M., Rowley, S., Salazar, C., Xing, Z., Allan, P. E., Bowtell, D. D. L., Mes-Masson, A. M., Provencher, D. M., Rahimi, K., Kelemen, L. E., Fasching, P. A., Doherty, J. A., Goodman, M. T., Goode, E. L., Deen, S., ... GAMuT Collaborators (2021). Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses. Modern Pathology, 34(1), 194-206. https://doi.org/10.1038/s41379-020-0618-9

Kang, Eun Young ; Cheasley, Dane ; LePage, Cecile ; Wakefield, Matthew J. ; da Cunha Torres, Michelle ; Rowley, Simone ; Salazar, Carolina ; Xing, Zhongyue ; Allan, Prue E. ; Bowtell, David D.L. ; Mes-Masson, Anne Marie ; Provencher, Diane M. ; Rahimi, Kurosh ; Kelemen, Linda E. ; Fasching, Peter A. ; Doherty, Jennifer A. ; Goodman, Marc T. ; Goode, Ellen L. ; Deen, Suha ; Pharoah, Paul D.P. ; Brenton, James D. ; Sieh, Weiva ; Mateoiu, Constantina ; Sundfeldt, Karin ; Cook, Linda S. ; Le, Nhu D. ; Anglesio, Michael S. ; Gilks, C. Blake ; Huntsman, David G. ; Kennedy, Catherine J. ; Traficante, Nadia ; DeFazio, Anna ; Kaufmann, Scott H. ; Churchman, Michael ; Gourley, Charlie ; Stephens, Andrew N. ; Meagher, Nicola S. ; Ramus, Susan J. ; Antill, Yoland C. ; Campbell, Ian ; Scott, Clare L. ; Köbel, Martin ; Gorringe, Kylie L. ; Australian Ovarian Cancer Study Group (AOCS) ; GAMuT Collaborators. / Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors : implications for outcome analyses. In: Modern Pathology. 2021 ; Vol. 34, No. 1. pp. 194-206.

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title = "Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses",

abstract = "TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.",

author = "Kang, {Eun Young} and Dane Cheasley and Cecile LePage and Wakefield, {Matthew J.} and {da Cunha Torres}, Michelle and Simone Rowley and Carolina Salazar and Zhongyue Xing and Allan, {Prue E.} and Bowtell, {David D.L.} and Mes-Masson, {Anne Marie} and Provencher, {Diane M.} and Kurosh Rahimi and Kelemen, {Linda E.} and Fasching, {Peter A.} and Doherty, {Jennifer A.} and Goodman, {Marc T.} and Goode, {Ellen L.} and Suha Deen and Pharoah, {Paul D.P.} and Brenton, {James D.} and Weiva Sieh and Constantina Mateoiu and Karin Sundfeldt and Cook, {Linda S.} and Le, {Nhu D.} and Anglesio, {Michael S.} and Gilks, {C. Blake} and Huntsman, {David G.} and Kennedy, {Catherine J.} and Nadia Traficante and Georgia Chenevix-Trench and A. Green and P. Webb and D. Gertig and Sian Fereday and S. Moore and J. Hung and K. Harrap and T. Sadkowsky and N. Pandeya and M. Malt and A. Mellon and R. Robertson and Bergh, {T. Vanden} and M. Jones and P. Mackenzie and J. Maidens and K. Nattress and Chiew, {Yoke Eng} 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 Joy Hendley and Kathryn 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 Hacker, {Neville F.} 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 P. Harnett and R. Sharma 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{\textquoteright}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 Anna DeFazio and Kaufmann, {Scott H.} and Michael Churchman and Charlie Gourley and Stephens, {Andrew N.} and Meagher, {Nicola S.} and Ramus, {Susan J.} and Antill, {Yoland C.} and Ian Campbell and Scott, {Clare L.} and Martin K{\"o}bel and Gorringe, {Kylie L.} and Ryland, {Georgina L.} and Kathryn Alsop and Sumitra Ananda and George Au-Yeung and Maret B{\"o}hm and Alison Brand and Georgia Chenevix-Trench and Michael Christie and Chiew, {Yoke Eng} and Rhiannon Dudley and Nicole Fairweather and Sian Fereday and Fox, {Stephen B.} and Hacker, {Neville F.} and Hadley, {Alison M.} and Joy Hendley and Ho, {Gwo Yaw} and Hunter, {Sally M.} and Kalli, {Kimberly R.} and {Le Page}, Cecile and McNally, {Orla M.} and McAlpine, {Jessica N.} and Linda Mileshkin and {Jan Pyman}, Pyman and Goli Samimi and Ragwha Sharma and {Australian Ovarian Cancer Study Group (AOCS)} and {GAMuT Collaborators}",

year = "2021",

month = jan,

doi = "10.1038/s41379-020-0618-9",

language = "English",

volume = "34",

pages = "194--206",

journal = "Modern Pathology",

issn = "0893-3952",

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Kang, EY, Cheasley, D, LePage, C, Wakefield, MJ, da Cunha Torres, M, Rowley, S, Salazar, C, Xing, Z, Allan, PE, Bowtell, DDL, Mes-Masson, AM, Provencher, DM, Rahimi, K, Kelemen, LE, Fasching, PA, Doherty, JA, Goodman, MT, Goode, EL, Deen, S, Pharoah, PDP, Brenton, JD, Sieh, W, Mateoiu, C, Sundfeldt, K, Cook, LS, Le, ND, Anglesio, MS, Gilks, CB, Huntsman, DG, Kennedy, CJ, Traficante, N, DeFazio, A, Kaufmann, SH, Churchman, M, Gourley, C, Stephens, AN, Meagher, NS, Ramus, SJ, Antill, YC, Campbell, I, Scott, CL, Köbel, M, Gorringe, KL, Australian Ovarian Cancer Study Group (AOCS) & GAMuT Collaborators 2021, 'Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses', Modern Pathology, vol. 34, no. 1, pp. 194-206. https://doi.org/10.1038/s41379-020-0618-9

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors : implications for outcome analyses. / Kang, Eun Young; Cheasley, Dane; LePage, Cecile; Wakefield, Matthew J.; da Cunha Torres, Michelle; Rowley, Simone; Salazar, Carolina; Xing, Zhongyue; Allan, Prue E.; Bowtell, David D.L.; Mes-Masson, Anne Marie; Provencher, Diane M.; Rahimi, Kurosh; Kelemen, Linda E.; Fasching, Peter A.; Doherty, Jennifer A.; Goodman, Marc T.; Goode, Ellen L.; Deen, Suha; Pharoah, Paul D.P.; Brenton, James D.; Sieh, Weiva; Mateoiu, Constantina; Sundfeldt, Karin; Cook, Linda S.; Le, Nhu D.; Anglesio, Michael S.; Gilks, C. Blake; Huntsman, David G.; Kennedy, Catherine J.; Traficante, Nadia; DeFazio, Anna; Kaufmann, Scott H.; Churchman, Michael; Gourley, Charlie; Stephens, Andrew N.; Meagher, Nicola S.; Ramus, Susan J.; Antill, Yoland C.; Campbell, Ian; Scott, Clare L.; Köbel, Martin; Gorringe, Kylie L.; Australian Ovarian Cancer Study Group (AOCS); GAMuT Collaborators.

In: Modern Pathology, Vol. 34, No. 1, 01.2021, p. 194-206.

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

TY - JOUR

T1 - Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors

T2 - implications for outcome analyses

AU - Kang, Eun Young

AU - Cheasley, Dane

AU - LePage, Cecile

AU - Wakefield, Matthew J.

AU - da Cunha Torres, Michelle

AU - Rowley, Simone

AU - Salazar, Carolina

AU - Xing, Zhongyue

AU - Allan, Prue E.

AU - Bowtell, David D.L.

AU - Mes-Masson, Anne Marie

AU - Provencher, Diane M.

AU - Rahimi, Kurosh

AU - Kelemen, Linda E.

AU - Fasching, Peter A.

AU - Doherty, Jennifer A.

AU - Goodman, Marc T.

AU - Goode, Ellen L.

AU - Deen, Suha

AU - Pharoah, Paul D.P.

AU - Brenton, James D.

AU - Sieh, Weiva

AU - Mateoiu, Constantina

AU - Sundfeldt, Karin

AU - Cook, Linda S.

AU - Le, Nhu D.

AU - Anglesio, Michael S.

AU - Gilks, C. Blake

AU - Huntsman, David G.

AU - Kennedy, Catherine J.

AU - Traficante, Nadia

AU - Chenevix-Trench, Georgia

AU - Green, A.

AU - Webb, P.

AU - Gertig, D.

AU - Fereday, Sian

AU - Moore, S.

AU - Hung, J.

AU - Harrap, K.

AU - Sadkowsky, T.

AU - Pandeya, N.

AU - Malt, M.

AU - Mellon, A.

AU - Robertson, R.

AU - Bergh, T. Vanden

AU - Jones, M.

AU - Mackenzie, P.

AU - Maidens, J.

AU - Nattress, K.

AU - Chiew, Yoke Eng

AU - Stenlake, A.

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AU - Brown, S.

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AU - Green, L.

AU - Jackman, L.

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AU - Martin, K.

AU - Martyn, A.

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AU - White, J.

AU - Jayde, V.

AU - Mamers, P.

AU - Bowes, L.

AU - Galletta, L.

AU - Giles, D.

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AU - Alsop, Kathryn

AU - Schmidt, T.

AU - Shirley, H.

AU - Ball, C.

AU - Young, C.

AU - Viduka, S.

AU - Tran, Hoa

AU - Bilic, Sanela

AU - Glavinas, Lydia

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AU - Rutovitz, J.

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AU - Glasgow, A.

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AU - Braye, S.

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AU - Au-Yeung, George

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AU - Brand, Alison

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AU - Christie, Michael

AU - Chiew, Yoke Eng

AU - Dudley, Rhiannon

AU - Fairweather, Nicole

AU - Fereday, Sian

AU - Fox, Stephen B.

AU - Hacker, Neville F.

AU - Hadley, Alison M.

AU - Hendley, Joy

AU - Ho, Gwo Yaw

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AU - McAlpine, Jessica N.

AU - Mileshkin, Linda

AU - Jan Pyman, Pyman

AU - Samimi, Goli

AU - Sharma, Ragwha

AU - Australian Ovarian Cancer Study Group (AOCS)

AU - GAMuT Collaborators

PY - 2021/1

Y1 - 2021/1

N2 - TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

AB - TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5–14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

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