MAGT1 deficiency increases polyomavirus susceptibility and risk of early-onset merkel cell carcinoma

Summary: Abstract Body: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, primarily caused by Merkel cell polyomavirus (MCPyV). MCC is a disease of advanced age (median age of diagnosis = 75 years) and is exceedingly rare in individuals under 30. Immune suppression also increases the risk of MCC, with 10% of patients being immunosuppressed. We previously identified three patients with X-linked immuno-deficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease who developed advanced-stage, MCPyV-positive MCC before the age of 25. XMEN disease is a rare primary immunodeficiency resulting from pathogenic loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. To investigate the association between XMEN and early-onset MCC, we analyzed the skin and serum of patients with XMEN. Shotgun metagenomic sequencing of the cutaneous microbiome revealed an elevated MCPyV burden, along with defects in controlling other polyomaviruses in XMEN patients. Consistent with this, XMEN patients exhibited elevated titers of neutralizing antibodies against MCPyV and other polyomaviruses. Remarkably, one patient who underwent allogeneic hematopoietic cell transplant continued to have elevated cutaneous MCPyV levels, even after full engraftment and discontinuation of immunosuppression. Persistently elevated virus in this patient suggests that MAGT1 function in non-hematopoietic cells is necessary for polyomavirus control. Collectively, our findings support the hypothesis that, although immunosuppression increases MCC risk, non-immune risk factors related to MCPyV susceptibility also contribute to the development of early-onset MCC in patients with XMEN. Yoshine Saito¹, Noreen Mohsin¹, Jennifer Strong¹, Austin J. Jabbour², Isaac Brownell¹ 1. Dermatology Branch, NIAMS, National Institutes of Health, Bethesda, MD, United States. 2. Department of Dermatology, New York Medical College, New York, NY, United States. UV Biology/Injury and Non-melanoma Cancers