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 | |
| Publication status | Published - Jan 2021 |
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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.
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, Joy
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
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, Neville F.
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 - Harnett, P.
AU - Sharma, 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 - DeFazio, Anna
AU - Kaufmann, Scott H.
AU - Churchman, Michael
AU - Gourley, Charlie
AU - Stephens, Andrew N.
AU - Meagher, Nicola S.
AU - Ramus, Susan J.
AU - Antill, Yoland C.
AU - Campbell, Ian
AU - Scott, Clare L.
AU - Köbel, Martin
AU - Gorringe, Kylie L.
AU - Ryland, Georgina L.
AU - Alsop, Kathryn
AU - Ananda, Sumitra
AU - Au-Yeung, George
AU - Böhm, Maret
AU - Brand, Alison
AU - Chenevix-Trench, Georgia
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
AU - Hunter, Sally M.
AU - Kalli, Kimberly R.
AU - Le Page, Cecile
AU - McNally, Orla M.
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.
UR - http://www.scopus.com/inward/record.url?scp=85100069475&partnerID=8YFLogxK
U2 - 10.1038/s41379-020-0618-9
DO - 10.1038/s41379-020-0618-9
M3 - Article
C2 - 32724153
AN - SCOPUS:85100069475
VL - 34
SP - 194
EP - 206
JO - Modern Pathology
JF - Modern Pathology
SN - 0893-3952
IS - 1
ER -