To describe a novel biomarker of germ-cell tumor and associated paraneoplastic neurological syndrome (PNS).
Archival sera from patients with germ-cell tumor associated PNS were evaluated. We identified a common autoantigen in a human testicular-cancer cell line (TCam-2) by western blot and mass spectrometry. Its identity was confirmed by recombinant-protein western blot, ELISA and cell based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/CSF.
Leucine zipper 4 (LUZP4)-IgG was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range 28-84). Median titer (ELISA) was 1:300 (1:50 to >1:6400; normal value <1:50). Co-existent Kelch-like protein 11-IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28; 61%). Other presentations included limbic encephalitis (n=5, 18%), seizures and/or encephalitis (n=2, 7%) and motor neuronopathy/polyradiculopathy (n=4, 14%). The most common malignancy among cancer-evaluated PNS patients was seminoma (21/27; 78%). Nine of the 21 seminomas detected by whole-body FDG-PET scan (43%) were extra-testicular. Both female patients had ovarian teratoma. Regressed testicular germ-cell tumors were found in four patients. Exposure of T-cell-dendritic-cell co-cultures from chronic immunosuppression naïve LUZP4-IgG-seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69-expression on both CD4+ and CD8+ T-cells when compared to vehicle-exposed and healthy control cultures.
LUZP4-IgG represents a novel serological biomarker of PNS and has high predictive value for germ-cell tumors. The demonstrated antigen-specific T-cell responses support a CD8+T-cell-mediated cytotoxic paraneoplastic and anti-tumor potential. This article is protected by copyright. All rights reserved.
Annals of neurology. 2021 Feb 14 [Epub ahead of print]
Divyanshu Dubey, Thomas Kryzer, Yong Guo, Benjamin Clarkson, John C Cheville, Brian A Costello, Bradley C Leibovich, Alicia Algeciras-Schimnich, Claudia Lucchinnetti, M Bakri Hammami, Andrew M Knight, Charles Howe, Vanda A Lennon, Andrew McKeon, Sean J Pittock
Department of Neurology, Mayo Clinic, Rochester., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester., Division of Medical Oncology, Mayo Clinic, Rochester., Department of Urology, Mayo Clinic, Rochester.