Identification of SKOR2 IgG as a Novel Biomarker of Paraneoplastic Neurologic Syndrome
Mohamed Rezk1, Sean Pittock1, Ronak Kapadia2, Andrew Knight1, Yong Guo1, Pranjal Gupta1, Reghann LaFrance-Corey1, Anastasia Zekeridou3, Andrew McKeon1, Surendra Dasari4, John Mills1, Divyanshu Dubey1
1Mayo Clinic Dept of Neuro, 2University of Calgary, 3Neuroimmunology Laboratory, Mayo Clinic, 4Mayo Clinic Dept of Biomedical Informatics
Objective:
To report identification of a novel biomarker of paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG.
Background:
PNS are group of disorders affecting any level of the neuroaxis associated with underlying tumors. Recently, wide variety of neurological presentations and autoantibodies have been associated with PNS. Development of novel autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq) has led to identification of novel putative autoantigens such as kelch-like protein 11 (KLHL11). Herein, we report the discovery of novel autoantibodies targeting SKOR2 protein in two patients diagnosed with CNS autoimmunity and underlying malignancy utilizing PhIP-Seq.
Design/Methods:
Stored specimens with unclassified staining at the junction of Purkinje cell and granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed utilizing recombinant antigen expressing cell-based assay (CBA), western blotting, and tissue immunofluorescence assay (IFA) colocalization. Additionally, we performed thorough clinical validation utilizing healthy and disease/cancer control samples.
Results:
PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed using recombinant SKOR2-expressing CBA, and cell lysate western blot. Furthermore, IgG from both patients’ samples colocalized with commercial SKOR2–specific IgG on mouse brain cryo-sections. Both the SKOR2-IgG positive patients had CNS involvement; one presenting with encephalitis and seizures (patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (patient 1: lung, patient 2: gall bladder). Histopathological assessment of the lung adenocarcinoma tissue (case 1) revealed cytoplasmic and nuclear SKOR2 immunoreactivity in the tumor cells. Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative.
Conclusions:
SKOR2-IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2-IgG positive cases will aid in categorization of associated neurological phenotype and risk of underlying malignancy.