MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma
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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Virchows ArchivInstitutions
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NCI NIH HHS Grant P50-CA135393Identifying Prognostic Markers and Therapeutic Targets for Serous Ovarian CancerLeadership, Planning and EvaluationCancer Research Career Enhancement and Related ActivitiesPathologyCancer Research Training and Education CoordinationCancer Risk Assessment, Early Detection, and Interception Research ProgramNCRR NIH HHS Grant MO1- RR000056Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskNCI NIH HHS Grant K07-CA80668Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskProject 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerRegulatory T Cell Function in Ovarian CancerCancer Research UK Grant 16561General Clinical Research CenterInflammation and Ovarian CancerOVARIAN CANCER RISK AND SURVIVAL IN BRCA CARRIERSInflammation and Ovarian CancerIdentifying Prognostic Markers and Therapeutic Targets for Serous Ovarian CancerAlberta Precision Laboratories Grant RS19-612Alberta Precision Laboratories Grant RS10-526Identifying Prognostic Markers and Therapeutic Targets for Serous Ovarian CancerNational Cancer Institute Grant K07-CA80668Inflammation and Ovarian CancerRegulatory T Cell Function in Ovarian CancerMedical Research and Materiel Command Grant DAMD17-02-1-0669National Center for Research Resources Grant MO1- RR000056Westmead Hospital Department of Gynaecological Oncology FundingNational Health and Medical Research Council Grant 310670National Health and Medical Research Council Grant 628903Cancer Institute NSW Grant 12/RIG/1-17Cancer Institute NSW Grant 15/RIG/1-16Sydney West Translational Cancer Research Centre FundingBreast Cancer Now FundingInstitute of Cancer Research FundingSwedish Cancer Foundation FundingU.S. Defense Health Program Grant HU0001-16-2-0006U.S. Defense Health Program Grant HU0001-19-2-0031BC Cancer Foundation FundingVGH and UBC Hospital Foundation FundingMichael Smith Foundation for Health Research FundingHeuer Stiftung für medizinische Forschung FundingUniversity of Pittsburgh Dean's Faculty Advancement Fund FundingAmerican Cancer Society Grant SIOP-06-258-01-COUNALF-agreement FundingAssar Gabrielsson Foundation FundingLeadership, Planning and EvaluationNational Cancer Institute Grant P50-CA135393Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and RiskNSW Ministry of Health FundingUniversity of New South Wales Grant NSW Health PhD Scholarship ProgramTranslational Cancer Research Network FundingDutch Cancer Society Grant IKNL2014-6838