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

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, Yague-Fernandez M, Edwards RP, Elishaev E, Olawaiye A, Taylor S, Ataseven B, Du Bois A, Harter P, Lester J, Hogdall 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 M, Rübner 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 P, 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, Hogdall 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, Kobel M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1007/s00428-021-03232-0

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-naive 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-naive tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naive 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.

Authors with CRIS profile

Involved external institutions

University of New South Wales (UNSW) Australia (AU) University of Western Australia (UWA) Australia (AU) University of Cambridge United Kingdom (GB) Oregon Health and Science University (OSHU) United States (USA) (US) Inova Health System United States (USA) (US) Prince of Wales Hospital (POWH) Australia (AU) Harvard University United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Mayo Clinic United States (USA) (US) Universitätsklinikum Tübingen Germany (DE) Brigham and Women's Hospital (BWH) United States (USA) (US) University of Gothenburg / Göteborgs universitet Sweden (SE) The Institute of Cancer Research (ICR) United Kingdom (GB) St John of God Subiaco Hospital Australia (AU) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University of Copenhagen Denmark (DK) University of Southern California (USC) United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) University of California Los Angeles (UCLA) United States (USA) (US) Beckman Research Institute of City of Hope (BRI) United States (USA) (US) Curtin University Australia (AU) Netherlands Cancer Institute (NKI) Netherlands (NL) HM Hospitales Spain (ES) University of Calgary Canada (CA) Danish Cancer Society Research Center Denmark (DK) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Roswell Park Cancer Institute United States (USA) (US) Westmead Institute for Medical Research Australia (AU) Royal Hospital for Women Australia (AU) University of Pittsburgh United States (USA) (US) University of Colorado System United States (USA) (US) Royal Alexandra Hospital (RAH) Canada (CA) Kliniken Essen-Mitte Germany (DE) University of British Columbia Canada (CA) S.C. Department of Health and Environmental Control United States (USA) (US) Uniformed Services University United States (USA) (US) BC Cancer Canada (CA) Westmead Hospital Australia (AU) University of Alberta Canada (CA) University of Chicago United States (USA) (US) Okayama University / 岡山大学 Japan (JP)

How to cite

APA:

Kang, E.Y., Millstein, J., Popovic, G., Meagher, N.S., Bolithon, A., Talhouk, A.,... Kobel, M. (2021). MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. Virchows Archiv. https://dx.doi.org/10.1007/s00428-021-03232-0

MLA:

Kang, Eun Young, et al. "MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma." Virchows Archiv (2021).

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