Autoantibody Profiling of Paraneoplastic Neurological Syndrome Sera Reveals ERVK7-IgG as a Germ Cell Tumor Associated Biomarker
Haidara Kherbek1, M Bakri Hammami2, Andrew Knight3, Brian Costello4, Silvana DeLorenzo3, Bradley Leibovich5, John Cheville3, Yong Guo6, Jessica Sagen3, Janet olson7, Alicia Algeciras-Schimnich3, Sean Pittock6, John Mills3, Surendra Dasari8, Divyanshu Dubey1
1Mayo Clinic Department of Neurology, Laboratory Medicine and Pathology, 2Mayo Clinic Department of Laboratory Medicine and Pathology/ H. Lee Moffitt Cancer Center Department of Hematology and Oncology, 3Mayo Clinic Department of Laboratory Medicine and Pathology, 4Mayo Clinic Department of Oncology, 5Mayo Clinic Department of Urology, 6Mayo Clinic Department of Neurology, 7Mayo Clinic Department of Quantitative Health Sciences, 8Mayo Clinic Department of Laboratory Medicine and Pathology and Department of Quantitative Health Sciences
Objective:
To identify novel autoantibody biomarkers in patients with paraneoplastic neurologic syndromes (PNS) associated with germ cell tumors (GCTs), and to evaluate their prevalence as GCT-specific serological markers in a broader tumor cohort.
Background:
Ma2-IgG, KLHL11-IgG, LUZP4-IgG and NMDA-R-IgG are known as GCT-related PNS autoantibodies. Leveraging tumor-specific immune response in PNS may enable discovery of GCT-specific biomarkers that improve tumor detection and disease monitoring.
Design/Methods:
Serum samples from patients with confirmed GCT-related PNS were screened using phage immunoprecipitation sequencing (PhIP-Seq) to identify cancer-specific IgGs. Candidate antigen was validated by enzyme-linked immunosorbent assay (ELISA), followed by testing in a larger GCT and other cancer cohort without PNS to assess tumor specificity.
Results:
Thirteen male patients (median age 48 years; range 29–84) with GCTs and KLHL11-IgG (n=12) and/or LUZP4-IgG (n=4) PNS were screened by PhIP-Seq, revealing antibody binding to distinct regions of the endogenous retrovirus group-K member-7 envelope protein (ERVK-7). In an independent set of 24 GCT-related PNS cases, 10 were ERVK-7-IgG–positive by ELISA, including 6 that were PhIP-Seq–positive. Among 358 GCT patients without PNS, 56 (16%) were ERVK-7-IgG positive, spanning multiple histologic subtypes most frequently seminoma (41%), followed by mixed GCT (21%) and embryonal carcinoma (18%). One ERVK-7-IgG positive woman had an ovarian teratoma. Specificity testing across autoimmune, oncologic, and healthy control sera showed minimal false positive rate (3/281, 1%). ERVK-7 expression was confirmed by IHC in GCT tissue, supporting tumor origin of the immune response.
Conclusions:
ERVK-7-IgG represents a novel GCT-associated autoantibody emerging from PNS cases and extending to broader GCT subsets, especially seminomas. Its detection may aid early diagnosis of GCTs, particularly in patients with neurologic symptoms or negative standard tumor markers. Notably, ERVK-7-IgG targets an endogenous retroviral envelope protein, suggesting an immune response against tumor-expressed endogenous retroviral antigens.
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