MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Eun Young Kang; Joshua Millstein; Gordana Popovic; Nicola S. Meagher; Adelyn Bolithon; Aline Talhouk; Derek S. Chiu; Michael S. Anglesio; Betty Leung; Katrina Tang; Neil Lambie; Marina Pavanello; Annalyn Da-anoy; Diether Lambrechts; Liselore Loverix; Siel Olbrecht; Christiani Bisinotto; Jesus Garcia-Donas; Sergio Ruiz-Llorente; Monica Yagüe-Fernandez; Robert P. Edwards; Esther Elishaev; Alexander Olawaiye; Sarah Taylor; Beyhan Ataseven; Andreas du Bois; Philipp Harter; Jenny Lester; Claus K. Høgdall; Sebastian M. Armasu; Yajue Huang; Robert A. Vierkant; Chen Wang; Stacey J. Winham; Sabine Heublein; Felix K.F. Kommoss; Daniel W. Cramer; Naoko Sasamoto; Lilian van-Wagensveld; Maria Lycke; Constantina Mateoiu; Janine Joseph; Malcolm C. Pike; Kunle Odunsi; Chiu Chen Tseng; Celeste L. Pearce; Sanela Bilic; Thomas P. Conrads; Arndt Hartmann; Alexander Hein; Michael E. Jones; Yee Leung; Matthias W. Beckmann; Matthias Ruebner; Minouk J. Schoemaker; Kathryn L. Terry; Mona A. El-Bahrawy; Penny Coulson; John L. Etter; Katherine LaVigne-Mager; Juergen Andress; Marcel Grube; Anna Fischer; Nina Neudeck; Greg Robertson; Rhonda Farrell; Ellen Barlow; Carmel Quinn; Anusha Hettiaratchi; Yovanni Casablanca; Ramona Erber; Colin J.R. Stewart; Adeline Tan; Yu Yu; Jessica Boros; Alison H. Brand; Paul R. Harnett; Catherine J. Kennedy; Nikilyn Nevins; Terry Morgan; Peter A. Fasching; Ignace Vergote; Anthony J. Swerdlow; Francisco J. Candido dos Reis; G. Larry Maxwell; Susan L. Neuhausen; Arantzazu Barquin-Garcia; Francesmary Modugno; Kirsten B. Moysich; Philip J. Crowe; Akira Hirasawa; Florian Heitz; Beth Y. Karlan; Ellen L. Goode; Peter Sinn; Hugo M. Horlings; Estrid Høgdall; Karin Sundfeldt; Stefan Kommoss; Annette Staebler; Anna H. Wu; Paul A. Cohen; Anna DeFazio; Cheng Han Lee; Helen Steed; Nhu D. Le; Simon A. Gayther; Kate Lawrenson; Paul D.P. Pharoah; Gottfried Konecny; Linda S. Cook; Susan J. Ramus; Linda E. Kelemen; Martin Köbel

doi:10.1007/s00428-021-03232-0

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Eun Young Kang, Joshua Millstein, Gordana Popovic, Nicola S. Meagher, Adelyn Bolithon, Aline Talhouk, Derek S. Chiu, Michael S. Anglesio, Betty Leung, Katrina Tang, Neil Lambie, Marina Pavanello, Annalyn Da-anoy, Diether Lambrechts, Liselore Loverix, Siel Olbrecht, Christiani Bisinotto, Jesus Garcia-Donas, Sergio Ruiz-Llorente, Monica Yagüe-FernandezRobert P. Edwards, Esther Elishaev, Alexander Olawaiye, Sarah Taylor, Beyhan Ataseven, Andreas du Bois, Philipp Harter, Jenny Lester, Claus K. Høgdall, Sebastian M. Armasu, Yajue Huang, Robert A. Vierkant, Chen Wang, Stacey J. Winham, Sabine Heublein, Felix K.F. Kommoss, Daniel W. Cramer, Naoko Sasamoto, Lilian van-Wagensveld, Maria Lycke, Constantina Mateoiu, Janine Joseph, Malcolm C. Pike, Kunle Odunsi, Chiu Chen Tseng, Celeste L. Pearce, Sanela Bilic, Thomas P. Conrads, Arndt Hartmann, Alexander Hein, Michael E. Jones, Yee Leung, Matthias W. Beckmann, Matthias Ruebner, Minouk J. Schoemaker, Kathryn L. Terry, Mona A. El-Bahrawy, Penny Coulson, John L. Etter, Katherine LaVigne-Mager, Juergen Andress, Marcel Grube, Anna Fischer, Nina Neudeck, Greg Robertson, Rhonda Farrell, Ellen Barlow, Carmel Quinn, Anusha Hettiaratchi, Yovanni Casablanca, Ramona Erber, Colin J.R. Stewart, Adeline Tan, Yu Yu, Jessica Boros, Alison H. Brand, Paul R. Harnett, Catherine J. Kennedy, Nikilyn Nevins, Terry Morgan, Peter A. Fasching, Ignace Vergote, Anthony J. Swerdlow, Francisco J. Candido dos Reis, G. Larry Maxwell, Susan L. Neuhausen, Arantzazu Barquin-Garcia, Francesmary Modugno, Kirsten B. Moysich, Philip J. Crowe, Akira Hirasawa, Florian Heitz, Beth Y. Karlan, Ellen L. Goode, Peter Sinn, Hugo M. Horlings, Estrid Høgdall, Karin Sundfeldt, Stefan Kommoss, Annette Staebler, Anna H. Wu, Paul A. Cohen, Anna DeFazio, Cheng Han Lee, Helen Steed, Nhu D. Le, Simon A. Gayther, Kate Lawrenson, Paul D.P. Pharoah, Gottfried Konecny, Linda S. Cook, Susan J. Ramus, Linda E. Kelemen, Martin Köbel^*

^*Corresponding author for this work

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

3 Scopus citations

Abstract

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Original language	English
Pages (from-to)	855-871
Number of pages	17
Journal	Virchows Archiv
Volume	480
Issue number	4
DOIs	https://doi.org/10.1007/s00428-021-03232-0
State	Published - Apr 2022
Externally published	Yes

Keywords

High-grade serous carcinoma
MCM3
Proliferation

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10.1007/s00428-021-03232-0

Cite this

Kang, E. Y., Millstein, J., Popovic, G., Meagher, N. S., Bolithon, A., Talhouk, A., Chiu, D. S., Anglesio, M. S., Leung, B., Tang, K., Lambie, N., Pavanello, M., Da-anoy, A., Lambrechts, D., Loverix, L., Olbrecht, S., Bisinotto, C., Garcia-Donas, J., Ruiz-Llorente, S., ... Köbel, M. (2022). MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. Virchows Archiv, 480(4), 855-871. https://doi.org/10.1007/s00428-021-03232-0

@article{e3f132e4993943db9eb9674b0d1f0e56,

title = "MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma",

abstract = "Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-na{\"i}ve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-na{\"i}ve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-na{\"i}ve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.",

keywords = "High-grade serous carcinoma, MCM3, Proliferation",

author = "Kang, {Eun Young} and Joshua Millstein and Gordana Popovic and Meagher, {Nicola S.} and Adelyn Bolithon and Aline Talhouk and Chiu, {Derek S.} and Anglesio, {Michael S.} and Betty Leung and Katrina Tang and Neil Lambie and Marina Pavanello and Annalyn Da-anoy and Diether Lambrechts and Liselore Loverix and Siel Olbrecht and Christiani Bisinotto and Jesus Garcia-Donas and Sergio Ruiz-Llorente and Monica Yag{\"u}e-Fernandez and Edwards, {Robert P.} and Esther Elishaev and Alexander Olawaiye and Sarah Taylor and Beyhan Ataseven and {du Bois}, Andreas and Philipp Harter and Jenny Lester and H{\o}gdall, {Claus K.} and Armasu, {Sebastian M.} and Yajue Huang and Vierkant, {Robert A.} and Chen Wang and Winham, {Stacey J.} and Sabine Heublein and Kommoss, {Felix K.F.} and Cramer, {Daniel W.} and Naoko Sasamoto and Lilian van-Wagensveld and Maria Lycke and Constantina Mateoiu and Janine Joseph and Pike, {Malcolm C.} and Kunle Odunsi and Tseng, {Chiu Chen} and Pearce, {Celeste L.} and Sanela Bilic and Conrads, {Thomas P.} and Arndt Hartmann and Alexander Hein and Jones, {Michael E.} and Yee Leung and Beckmann, {Matthias W.} and Matthias Ruebner and Schoemaker, {Minouk J.} and Terry, {Kathryn L.} and El-Bahrawy, {Mona A.} and Penny Coulson and Etter, {John L.} and Katherine LaVigne-Mager and Juergen Andress and Marcel Grube and Anna Fischer and Nina Neudeck and Greg Robertson and Rhonda Farrell and Ellen Barlow and Carmel Quinn and Anusha Hettiaratchi and Yovanni Casablanca and Ramona Erber and Stewart, {Colin J.R.} and Adeline Tan and Yu Yu and Jessica Boros and Brand, {Alison H.} and Harnett, {Paul R.} and Kennedy, {Catherine J.} and Nikilyn Nevins and Terry Morgan and Fasching, {Peter A.} and Ignace Vergote and Swerdlow, {Anthony J.} and {Candido dos Reis}, {Francisco J.} and Maxwell, {G. Larry} and Neuhausen, {Susan L.} and Arantzazu Barquin-Garcia and Francesmary Modugno and Moysich, {Kirsten B.} and Crowe, {Philip J.} and Akira Hirasawa and Florian Heitz and Karlan, {Beth Y.} and Goode, {Ellen L.} and Peter Sinn and Horlings, {Hugo M.} and Estrid H{\o}gdall and Karin Sundfeldt and Stefan Kommoss and Annette Staebler and Wu, {Anna H.} and Cohen, {Paul A.} and Anna DeFazio and Lee, {Cheng Han} and Helen Steed and Le, {Nhu D.} and Gayther, {Simon A.} and Kate Lawrenson and Pharoah, {Paul D.P.} and Gottfried Konecny and Cook, {Linda S.} and Ramus, {Susan J.} and Kelemen, {Linda E.} and Martin K{\"o}bel",

note = "Funding Information: The authors have no relevant conflicts of interest regarding this publication. A. Hartmann has received honoraria from BMS, MSD, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Jansen-Cilag, and Ipsen. R. Erber has received honoraria from Roche, Eisai, Pfizer, and Novartis and travel grants from BioNTech. The institution of A. Hartmann and R. Erber conducts research for AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Novartis, Cepheid, and BioNTech. P. Harter{\textquoteright}s honoraria: Astra Zeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis Advisory Board: Astra Zeneca, Roche, GSK, Clovis, Immunogen, MSD/Merck Research Funding (Inst): Astra Zeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Clovis. T.P. Conrads is member of the Thermo Fisher Scientific Inc. scientific advisory board. P. A. Cohen received honoraria from Seqirus and Astra Zeneca. Funding Information: For all participating studies, we thank all the women who participated in research, study staff, doctors, nurses, health care providers, and health information sources who have contributed to the study. We thank Shuhong Liu and Young Ou from the Anatomical Pathology Research Laboratory at the University of Calgary for performing immunohistochemistry, and Thomas Kryton, image specialist, for compiling the composite figures. We thank all the women who participated in the GynBiobank, and gratefully acknowledge the Departments of Gynaecological Oncology, Medical Oncology and Anatomical Pathology at Westmead Hospital, Sydney. The Health Science Alliance (HSA) Biobank acknowledges the UNSW Biorepository, UNSW Sydney, Australia. Funding Information: M. K{\"o}bel received internal support through the Alberta Precision Laboratory research support fund (RS19-612, RS10-526). This work was funded by the National Institutes of Health/National Cancer Institute (NCI) Grants to S.J. Ramus [grant number R01CA172404]. J. Millstein is funded by NCI grant P30CA014089. S. Heublein was funded by Heuer Stiftung f{\"u}r medizinische Forschung. N.S. Meagher is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research center program funded by the Cancer Institute NSW. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. BC's Gynecological Cancer Research team (OVCARE) receives support through the BC Cancer Foundation and The VGH + UBC Hospital Foundation. Funding Information: The HOP study was funded by the US National Cancer Institute K07-CA80668 (F. Modugno), R01CA095023 (F. Modugno), R01 CA126841 (K.B. Moysich), US Army Medical Research and Materiel Command DAMD17-02–1-0669 (F. Modugno), NIH/National Center for Research Resources/General Clinical Research Center grant MO1- RR000056, and the University of Pittsburgh Dean's Faculty Advancement Fund (F. Modugno). B. Karlan was supported in part by the American Cancer Society SIOP-06–258-01-COUN. The WMH study was supported by the Westmead Hospital Department of Gynaecological Oncology. The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling Grants ID 310,670 & ID 628,903 and the Cancer Institute NSW Grants ID 12/RIG/1–17 & 15/RIG/1–16. The Westmead GynBiobank acknowledges financial support from the West Translational Cancer Research Centre. The Sydney West Translational Cancer Research Centre is funded by the Cancer Institute NSW. The BGS study is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The SWE study, K. Sundfeldt, C. Mateoiu, and the GynCancer Biobank in Western Sweden are financed by Swedish Cancer foundation (K. Sundfeldt), Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement (K. Sundfeldt) and Assar Gabrielsson foundation (C. Mateoiu). The GYN-COE program, T.P. Conrads, Y. Cassablanca, and G.L. Maxwell, are funded by the U.S. Defense Health Program (grants HU0001-16–2-0006 and HU0001-19–2-0031). The MAY study was supported by P50-CA135393 and R01-CA248288. The HSA Biobank, UNSW Biorepository, UNSW Sydney, Australia, is funded by the Translational Cancer Research Network (TCRN), a Translational Cancer Research Centre supported by the Cancer Institute NSW. The work of the IKNL-NKI was supported by Dutch Cancer Society [IKNL2014-6838]. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2022",

month = apr,

doi = "10.1007/s00428-021-03232-0",

language = "English",

volume = "480",

pages = "855--871",

journal = "Virchows Archiv",

issn = "0945-6317",

number = "4",

}

Kang, EY, Millstein, J, Popovic, G, Meagher, NS, Bolithon, A, Talhouk, A, Chiu, DS, Anglesio, MS, Leung, B, Tang, K, Lambie, N, Pavanello, M, Da-anoy, A, Lambrechts, D, Loverix, L, Olbrecht, S, Bisinotto, C, Garcia-Donas, J, Ruiz-Llorente, S, Yagüe-Fernandez, M, Edwards, RP, Elishaev, E, Olawaiye, A, Taylor, S, Ataseven, B, du Bois, A, Harter, P, Lester, J, Høgdall, CK, Armasu, SM, Huang, Y, Vierkant, RA, Wang, C, Winham, SJ, Heublein, S, Kommoss, FKF, Cramer, DW, Sasamoto, N, van-Wagensveld, L, Lycke, M, Mateoiu, C, Joseph, J, Pike, MC, Odunsi, K, Tseng, CC, Pearce, CL, Bilic, S, Conrads, TP, Hartmann, A, Hein, A, Jones, ME, Leung, Y, Beckmann, MW, Ruebner, M, Schoemaker, MJ, Terry, KL, El-Bahrawy, MA, Coulson, P, Etter, JL, LaVigne-Mager, K, Andress, J, Grube, M, Fischer, A, Neudeck, N, Robertson, G, Farrell, R, Barlow, E, Quinn, C, Hettiaratchi, A, Casablanca, Y, Erber, R, Stewart, CJR, Tan, A, Yu, Y, Boros, J, Brand, AH, Harnett, PR, Kennedy, CJ, Nevins, N, Morgan, T, Fasching, PA, Vergote, I, Swerdlow, AJ, Candido dos Reis, FJ, Maxwell, GL, Neuhausen, SL, Barquin-Garcia, A, Modugno, F, Moysich, KB, Crowe, PJ, Hirasawa, A, Heitz, F, Karlan, BY, Goode, EL, Sinn, P, Horlings, HM, Høgdall, E, Sundfeldt, K, Kommoss, S, Staebler, A, Wu, AH, Cohen, PA, DeFazio, A, Lee, CH, Steed, H, Le, ND, Gayther, SA, Lawrenson, K, Pharoah, PDP, Konecny, G, Cook, LS, Ramus, SJ, Kelemen, LE & Köbel, M 2022, 'MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma', Virchows Archiv, vol. 480, no. 4, pp. 855-871. https://doi.org/10.1007/s00428-021-03232-0

TY - JOUR

T1 - MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

AU - Kang, Eun Young

AU - Millstein, Joshua

AU - Popovic, Gordana

AU - Meagher, Nicola S.

AU - Bolithon, Adelyn

AU - Talhouk, Aline

AU - Chiu, Derek S.

AU - Anglesio, Michael S.

AU - Leung, Betty

AU - Tang, Katrina

AU - Lambie, Neil

AU - Pavanello, Marina

AU - Da-anoy, Annalyn

AU - Lambrechts, Diether

AU - Loverix, Liselore

AU - Olbrecht, Siel

AU - Bisinotto, Christiani

AU - Garcia-Donas, Jesus

AU - Ruiz-Llorente, Sergio

AU - Yagüe-Fernandez, Monica

AU - Edwards, Robert P.

AU - Elishaev, Esther

AU - Olawaiye, Alexander

AU - Taylor, Sarah

AU - Ataseven, Beyhan

AU - du Bois, Andreas

AU - Harter, Philipp

AU - Lester, Jenny

AU - Høgdall, Claus K.

AU - Armasu, Sebastian M.

AU - Huang, Yajue

AU - Vierkant, Robert A.

AU - Wang, Chen

AU - Winham, Stacey J.

AU - Heublein, Sabine

AU - Kommoss, Felix K.F.

AU - Cramer, Daniel W.

AU - Sasamoto, Naoko

AU - van-Wagensveld, Lilian

AU - Lycke, Maria

AU - Mateoiu, Constantina

AU - Joseph, Janine

AU - Pike, Malcolm C.

AU - Odunsi, Kunle

AU - Tseng, Chiu Chen

AU - Pearce, Celeste L.

AU - Bilic, Sanela

AU - Conrads, Thomas P.

AU - Hartmann, Arndt

AU - Hein, Alexander

AU - Jones, Michael E.

AU - Leung, Yee

AU - Beckmann, Matthias W.

AU - Ruebner, Matthias

AU - Schoemaker, Minouk J.

AU - Terry, Kathryn L.

AU - El-Bahrawy, Mona A.

AU - Coulson, Penny

AU - Etter, John L.

AU - LaVigne-Mager, Katherine

AU - Andress, Juergen

AU - Grube, Marcel

AU - Fischer, Anna

AU - Neudeck, Nina

AU - Robertson, Greg

AU - Farrell, Rhonda

AU - Barlow, Ellen

AU - Quinn, Carmel

AU - Hettiaratchi, Anusha

AU - Casablanca, Yovanni

AU - Erber, Ramona

AU - Stewart, Colin J.R.

AU - Tan, Adeline

AU - Yu, Yu

AU - Boros, Jessica

AU - Brand, Alison H.

AU - Harnett, Paul R.

AU - Kennedy, Catherine J.

AU - Nevins, Nikilyn

AU - Morgan, Terry

AU - Fasching, Peter A.

AU - Vergote, Ignace

AU - Swerdlow, Anthony J.

AU - Candido dos Reis, Francisco J.

AU - Maxwell, G. Larry

AU - Neuhausen, Susan L.

AU - Barquin-Garcia, Arantzazu

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Crowe, Philip J.

AU - Hirasawa, Akira

AU - Heitz, Florian

AU - Karlan, Beth Y.

AU - Goode, Ellen L.

AU - Sinn, Peter

AU - Horlings, Hugo M.

AU - Høgdall, Estrid

AU - Sundfeldt, Karin

AU - Kommoss, Stefan

AU - Staebler, Annette

AU - Wu, Anna H.

AU - Cohen, Paul A.

AU - DeFazio, Anna

AU - Lee, Cheng Han

AU - Steed, Helen

AU - Le, Nhu D.

AU - Gayther, Simon A.

AU - Lawrenson, Kate

AU - Pharoah, Paul D.P.

AU - Konecny, Gottfried

AU - Cook, Linda S.

AU - Ramus, Susan J.

AU - Kelemen, Linda E.

AU - Köbel, Martin

N1 - Funding Information: The authors have no relevant conflicts of interest regarding this publication. A. Hartmann has received honoraria from BMS, MSD, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Jansen-Cilag, and Ipsen. R. Erber has received honoraria from Roche, Eisai, Pfizer, and Novartis and travel grants from BioNTech. The institution of A. Hartmann and R. Erber conducts research for AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Novartis, Cepheid, and BioNTech. P. Harter’s honoraria: Astra Zeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis Advisory Board: Astra Zeneca, Roche, GSK, Clovis, Immunogen, MSD/Merck Research Funding (Inst): Astra Zeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Clovis. T.P. Conrads is member of the Thermo Fisher Scientific Inc. scientific advisory board. P. A. Cohen received honoraria from Seqirus and Astra Zeneca. Funding Information: For all participating studies, we thank all the women who participated in research, study staff, doctors, nurses, health care providers, and health information sources who have contributed to the study. We thank Shuhong Liu and Young Ou from the Anatomical Pathology Research Laboratory at the University of Calgary for performing immunohistochemistry, and Thomas Kryton, image specialist, for compiling the composite figures. We thank all the women who participated in the GynBiobank, and gratefully acknowledge the Departments of Gynaecological Oncology, Medical Oncology and Anatomical Pathology at Westmead Hospital, Sydney. The Health Science Alliance (HSA) Biobank acknowledges the UNSW Biorepository, UNSW Sydney, Australia. Funding Information: M. Köbel received internal support through the Alberta Precision Laboratory research support fund (RS19-612, RS10-526). This work was funded by the National Institutes of Health/National Cancer Institute (NCI) Grants to S.J. Ramus [grant number R01CA172404]. J. Millstein is funded by NCI grant P30CA014089. S. Heublein was funded by Heuer Stiftung für medizinische Forschung. N.S. Meagher is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research center program funded by the Cancer Institute NSW. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. BC's Gynecological Cancer Research team (OVCARE) receives support through the BC Cancer Foundation and The VGH + UBC Hospital Foundation. Funding Information: The HOP study was funded by the US National Cancer Institute K07-CA80668 (F. Modugno), R01CA095023 (F. Modugno), R01 CA126841 (K.B. Moysich), US Army Medical Research and Materiel Command DAMD17-02–1-0669 (F. Modugno), NIH/National Center for Research Resources/General Clinical Research Center grant MO1- RR000056, and the University of Pittsburgh Dean's Faculty Advancement Fund (F. Modugno). B. Karlan was supported in part by the American Cancer Society SIOP-06–258-01-COUN. The WMH study was supported by the Westmead Hospital Department of Gynaecological Oncology. The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling Grants ID 310,670 & ID 628,903 and the Cancer Institute NSW Grants ID 12/RIG/1–17 & 15/RIG/1–16. The Westmead GynBiobank acknowledges financial support from the West Translational Cancer Research Centre. The Sydney West Translational Cancer Research Centre is funded by the Cancer Institute NSW. The BGS study is funded by Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The SWE study, K. Sundfeldt, C. Mateoiu, and the GynCancer Biobank in Western Sweden are financed by Swedish Cancer foundation (K. Sundfeldt), Swedish state under the agreement between the Swedish government and the county council, the ALF-agreement (K. Sundfeldt) and Assar Gabrielsson foundation (C. Mateoiu). The GYN-COE program, T.P. Conrads, Y. Cassablanca, and G.L. Maxwell, are funded by the U.S. Defense Health Program (grants HU0001-16–2-0006 and HU0001-19–2-0031). The MAY study was supported by P50-CA135393 and R01-CA248288. The HSA Biobank, UNSW Biorepository, UNSW Sydney, Australia, is funded by the Translational Cancer Research Network (TCRN), a Translational Cancer Research Centre supported by the Cancer Institute NSW. The work of the IKNL-NKI was supported by Dutch Cancer Society [IKNL2014-6838]. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2022/4

Y1 - 2022/4

N2 - Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

AB - Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

KW - High-grade serous carcinoma

KW - MCM3

KW - Proliferation

UR - http://www.scopus.com/inward/record.url?scp=85119070861&partnerID=8YFLogxK

U2 - 10.1007/s00428-021-03232-0

DO - 10.1007/s00428-021-03232-0

M3 - Article

C2 - 34782936

AN - SCOPUS:85119070861

SN - 0945-6317

VL - 480

SP - 855

EP - 871

JO - Virchows Archiv

JF - Virchows Archiv

IS - 4

ER -

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

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