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.
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References
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Acknowledgements
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
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.
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].
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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.
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Kang, E.Y., Millstein, J., Popovic, G. et al. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. Virchows Arch 480, 855–871 (2022). https://doi.org/10.1007/s00428-021-03232-0
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DOI: https://doi.org/10.1007/s00428-021-03232-0