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.
OBJECTIVE
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.


METHODS
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.
Söling
Ariane
A
Department of Neurosurgery, Martin Luther University Halle-Wittenberg, Halle, Germany. ariane.soeling@medizin.uni-halle.de
Sackewitz
Mirko
M
Volkmar
Michael
M
Schaarschmidt
Daniel
D
Jacob
Roland
R
Holzhausen
Hans-Jürgen
HJ
Rainov
Nikolai G
NG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism; D001254:Astrocytoma / Q000276:immunology* / Q000378:metabolism / Q000401:mortality*; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality*; D018797:Cell Cycle Proteins; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018572:Disease-Free Survival; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D064126:Minichromosome Maintenance Complex Component 3; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D016896:Treatment Outcome
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C066470:MCM3 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D064126:Minichromosome Maintenance Complex Component 3