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

Kang, Eun Young; Page, Cécile Le; Torres, Michelle da Cunha; Rowley, Simone M.; Salazar, Carolina; Xing, Zhongyue; 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.; Chenevix-Trench, G.; Green, A.; Webb, Penelope M.; deFazio, Anna; Gertig, Dorota M.; Fereday, Sián; Moore, Samantha; Hung, Jillian; Harrap, K. R.; Sadkowsky, T.; Pandeya, Neha; Malt, M.; Mellon, A.; Robertson, R. Paul; Bergh, T. Vanden; Jones, Michael E.; Mackenzie, P.; Maidens, Jayne; Nattress, Kathryn; Chiew, Yoke Eng; Stenlake, Annie; Sullivan, Harold C.; Alexander, Barbara; Ashover, P.; Brown, Stephen M.; Corrish, T.; Green, L.; Jackman, L. M.; Ferguson, Kaltin; Martin, Karla; Martyn, A.; Ranieri, B.; White, Jeff; Jayde, V.; Mamers, Pam; Bowes, Leanne; Galletta, Laura; Giles, Daniel; Hendley, Joy; Alsop, Kathryn; Schmidt, Tannin A.; Shirley, H.; Ball, Catherine A.; Young, Christian D.; Viduka, S.; Tran, Hoa Thi Tuyet; Bilic, Sanela; Glavinas, Lydia; Brooks, Julia; Stuart-Harris, R.; Kirsten, Fred; Rutovitz, J.; Clingan, P.; Glasgow, Akisha; Proietto, Anthony; Braye, Stephen; Otton, Geoffrey; Shannon, Jenny; Bonaventura, Tony; Stewart, Jocelyn M.; Begbie, Stephen; Friedländer, M.; Bell, Debra A.; Baron‐Hay, Sally; Ferrier, A.; Gard, Gregory B.; Nevell, David; Pavlakis, Nick; Valmadre, Susan; Young, B.; Camaris, Catherine; Crouch, Roger; Edwards, L.; Hacker, Neville F.; Marsden, Donald E.; Robertson, Gregory; Beale, Philip; Beith, Jane; Carter, J.; Dalrymple, Chris; Houghton, R.; Russell, Prudence A.; Links, Matthew; Grygiel, John J.; Hill, Jane; Byth, Karen; Jaworski, Richard; Harnett, Paul; Sharma, R.; Wain, Gerard; Ward, BG; Papadimos, David; Crandon, Alexander J.; Cummings, Michael P.; Horwood, Keith; Obermair, A.; Perrin, Lewis; Wyld, David; Nicklin, Jim; Davy, Marcus; Oehler, Martin K.; Hall, Cathrine; Dodd, Tom; Healy, Timothy M.; Pittman, Keir; Henderson, D. C.; Miller, J.; Pierdes, J.; Blomfield, Penny; Challis, D.; McIntosh, Rachel; Parker, Alyssa; Brown, Bob D.; Rome, Robert M.; Allen, Digby; Grant, Peter; Hyde, Simon; Laurie, R.; Robbie, Melissa; Healy, David; Jobling, Tom; Manolitsas, Thomas; McNealage, J.; Rogers, Peter A. W.; Susil, B.; Sumithran, Eric; Simpson, Ian; Phillips, Kelly‐Anne; Rischin, Danny; Fox, Stephen B.; Johnson, Daryl; Lade, Stephen; Loughrey, Maurice B.; O’Callaghan, Neil; Murray, William K.; Waring, Paul; Billson, Virginia; Pyman, Jan; Neesham, Deborah; Quinn, Michael C.; Underhill, Craig; Bell, Rachel E.; Ng, L.F.; Blum, Robert; Ganju, Vinod; Hammond, Ian; Leung, Yee; McCartney, Anthony J.; Buck, Martin; Haviv, Izhak; Purdie, D. M.; Whiteman, DC; Zeps, Nikolajs; Meagher, Nicola S.; Ramus, Susan J.; Cheasley, Dane; Wakefield, Matthew; Ryland, Georgina L; Allan, Prue E.; Ananda, Sumitra; Anglesio, Michael S.; Au-Yeung, George; Böhm, Maret; Bowtell, David D.; Brand, Alison; Chenevix‐Trench, Georgia; Christie, Michael; Chiew, Yoke-Eng; Churchman, Michael; deFazio, Anna; Dudley, Rhiannon; Fairweather, Nicole; Gilks, C. Blake; Gourley, Charlie; Hadley, Alison; Ho, Gwo-Yaw; Huntsman, David G.; Hunter, Sally M.; Kalli, Kimberly R.; Kaufmann, Scott H.; Kennedy, Catherine J.; Köbel, Martin; Page, Cécile Le; McNally, Orla; McAlpine, Jessica N.; Mes‐Masson, Anne‐Marie; Mileshkin, Linda; Provencher, Diane; Rahimi, Kurosh; Samimi, Goli; Stephens, Andrew N.; Traficante, Nadia; Antill, Yoland; Scott, Clare L.; Campbell, Ian G.; Gorringe, Kylie L.

doi:10.1038/s41379-020-0618-9

Cited by 25 publications

(20 citation statements)

References 19 publications

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“…For example, as ovarian mucinous neoplasms progress from borderline to carcinoma, they can acquire a TP53 mutation. 43 Two of the current study authors (W.G.M. and C.J.R.S.)…”

Section: Discussionmentioning

confidence: 89%

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p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

et al. 2021

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p53 immunohistochemical analysis of fusion-positive uterine sarcomas Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas. Methods and results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/ rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression. Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours.

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“…For example, as ovarian mucinous neoplasms progress from borderline to carcinoma, they can acquire a TP53 mutation. 43 Two of the current study authors (W.G.M. and C.J.R.S.)…”

Section: Discussionmentioning

confidence: 89%

“…The acquisition of a TP53 mutation during tumour progression has parallels in other gynaecological neoplasms. For example, as ovarian mucinous neoplasms progress from borderline to carcinoma, they can acquire a TP53 mutation 43 . Two of the current study authors (W.G.M.…”

Section: Discussionmentioning

confidence: 98%

p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

et al. 2021

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“…The prevalence we report herein is slightly higher (8.2%) than before (5.1%). In the current study, we used a very sensitive threshold according to our previous study to identify p53 subclonality [18]. We did this for two reasons: p53 subclonality, even if very focal, in the diagnostic setting supports a diagnosis of endometrioid carcinoma, and second, we hypothesized that subclonality could predict POLE mutation status.…”

Section: Discussionmentioning

confidence: 99%

Selection of endometrial carcinomas for p53 immunohistochemistry based on nuclear features

Kang

Aubrey

Lee

et al. 2021

The Journal of Pathology CR

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The World Health Organization endorses molecular subclassification of endometrial endometrioid carcinomas (EECs). Our objectives were to test the sensitivity of tumor morphology in capturing p53 abnormal (p53abn) cases and to model the impact of p53abn on changes to ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) risk stratification. A total of 292 consecutive endometrial carcinoma resections received at Foothills Medical Centre, Calgary, Canada (2019-2021) were retrieved and assigned to ESGO risk groups with and without p53 status. Three pathologists reviewed the representative H&E-stained slides, predicted the p53 status, and indicated whether p53 immunohistochemistry (IHC) would be ordered. Population-based survival for endometrial carcinomas diagnosed during 2008-2016 in Alberta was obtained from the Alberta Cancer Registry. The cohort consisted mostly of grade 1/2 endometrioid carcinomas (EEC1/2; N = 218, 74.6%). One hundred and fifty-two EEC1/2 (52.1% overall) were stage IA and 147 (50.3%) were low risk by ESGO. The overall prevalence of p53abn and subclonal p53 was 14.5 and 8.3%, respectively. The average sensitivity of predicting p53abn among observers was 83.6%. Observers requested p53 IHC for 39.4% with 98.5% sensitivity to detect p53abn (99.6% negative predictive value). Nuclear features including smudged chromatin, pleomorphism, atypical mitoses, and tumor giant cells accurately predicted p53abn. In 7/292 (2.4%), p53abn upgraded ESGO risk groups (2 to intermediate risk, 5 to high risk). EEC1/2/stage IA patients had an excellent disease-specific 5-year survival of 98.5%. Pathologists can select cases for p53 testing with high sensitivity and low risk of false negativity. Molecular characterization of endometrial carcinomas has great potential to refine ESGO risk classification for a small subset but offers little value for approximately half of endometrial carcinomas, namely, EEC1/2/stage IA cases.

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“…The largest study of ovarian mucinous carcinomas confirmed frequent copy number losses (hetero- or homozygous) of CDKN2A and mutations in CDKN2A and KRAS as early events [ 102 ]. The progression from borderline tumor to carcinoma is often associated with the acquisition of a TP53 mutation and additional copy number alterations [ 102 , 103 ]. In stark contrast to the dualistic pathway of serous carcinomas, KRAS and TP53 mutations often co-occur in ovarian MC, perhaps explaining the resistance to platinum–taxane chemotherapy.…”

Section: Molecular Subtypes Of Ovarian Carcinomasmentioning

confidence: 99%

The Evolution of Ovarian Carcinoma Subclassification

Köbel

Kang

2022

Cancers

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The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.

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

Cited by 25 publications

References 19 publications

p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

p53 immunohistochemical analysis of fusion‐positive uterine sarcomas

Selection of endometrial carcinomas for p53 immunohistochemistry based on nuclear features

The Evolution of Ovarian Carcinoma Subclassification

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