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Minichromosome Maintenance Protein 3 Elicits a Cancer-Restricted Immune Response in Patients with Brain Malignancies and Is a Strong Independent Predictor of Survival in Patients with Anaplastic Astrocytoma

¹ Department of Neurosurgery and Institutes of ² Biotechnology, ³ Genetics, and ⁴ Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany; ⁵ Department of Biology, University of Konstanz, Konstanz, Germany; and ⁶ Department of Neurological Science, University of Liverpool, Liverpool, United Kingdom

Requests for reprints: Ariane Söling, Molecular Neurooncology Laboratory, Department of Neurosurgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, FG 6/E01, D-06097 Halle, Germany. Phone: 49-345-5575285; Fax: 49-345-5575283; E-mail: ariane.soeling{at}medizin.uni-halle.de.

Purpose: The identification of new molecular markers in astrocytic tumors may help to understand the biology of these tumors in more detail. Informative tumor markers may represent prognostic factors for response to therapy and outcome as well as potential targets for novel anticancer therapies.

Experimental Design: Tumor-associated antigens were identified by immunoscreening of a human glioma cDNA expression library with allogeneic sera from patients with diffuse astrocytoma (WHO grades 2-4). The expression of one of the identified antigens, the replication licensing factor minichromosome maintenance protein 3 (MCM3), was analyzed by immunohistochemistry in 142 primary and 27 recurrent astrocytomas (WHO grades 2-4). In addition, 98 serum specimens from patients with primary and secondary brain malignancies and 30 serum specimens from healthy controls were examined by serologic immunoscreening for immunoreactivity with MCM3.

Results: MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in 9.3% (9 of 97) of patients with brain tumors (n = 95) and brain metastases (n = 2) but not in healthy controls. Expression of MCM3 in diffuse astrocytoma is significantly associated with age (P < 0.001), histologic grade (P < 0.001), time to recurrence (P = 0.01), and expression of the proliferation marker Ki-67 (P < 0.001) but not with sex (P = 0.800). Univariate and multivariate Cox regression analysis confirmed MCM3 expression as an independent predictor of poor outcome in astrocytoma patients (P < 0.001 for both).

Conclusions: MCM3 may represent a glioma-associated antigen with significant prognostic role as well as have some potential as a target for cancer-directed therapy.

Key Words: glioma • glioblastoma • prereplication complex • cancer • tumor

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