Abstract
EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy. We describe the largest single institution analysis in renal transplant recipients. It aims to define its clinical features and determine the expression of EBV latent genes as well as key molecular pathways. Patients with EBV+SMT were identified from the Singapore General Hospital Renal Transplant Registry database. These tumors were investigated for expression of EBV latent genes with Southern blots, EBV latent antigens, mammalian target of rapamycin (mTOR), Akt, p70 S6 kinase, and vascular endothelial growth factor using immunohistochemistry, as well as methylation status of cancer-related genes using methylation-specific PCR. Eight were found to be EBV+SMT in 1,123 transplant patients. All displayed indolent clinical courses and were unresponsive to immunosuppression reduction. Complete tumor regression was seen in one patient following administration of sirolimus. These tumors display the full range of known EBV latent genes. Immunohistochemistry with total and phosphorylated mTOR and Akt were positive for all patients, and vascular endothelial growth factor was positive in 25% of patients, suggesting activation of the mTOR/Akt pathway. Methylation of RASSF1A was found in all tissue samples, whereas promoter hypermethylation of RARbeta, GSTP1, DAPK, and p14 was observed in some samples. Our results suggest that these tumors display a EBV type III latency pattern. The mTOR pathway is also activated. EBV may play a role in silencing RASSF1A. EBV-specific immunotherapy, mTOR inhibitors, and demethylating agents are possible therapeutic options in this disease.
Highlights
EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy
The mammalian target of rapamycin pathway plays an important role in regulating cell growth and proliferation and its deregulation is associated with many human cancers and diabetes [3]
We studied the promoter hypermethylation status of seven genes, namely O6-methylguanine-DNA methyltransferase (MGMT), death-associated protein kinase (DAPK), retinoic receptor β gene (RARβ2), ras association domain family 1A (RASSF1A), p14 (ARF), p16 (CDNK2A), and glutathione S-transferase (GSTP1)
Summary
EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy. We describe the largest single institution analysis in renal transplant recipients It aims to define its clinical features and determine the expression of EBV latent genes as well as key molecular pathways. Experimental Design: Patients with EBV+SMT were identified from the Singapore General Hospital Renal Transplant Registry database These tumors were investigated for expression of EBV latent genes with Southern blots, EBV latent antigens, mammalian target of rapamycin (mTOR), Akt, p70 S6 kinase, and vascular endothelial growth factor using immunohistochemistry, as well as methylation status of cancer-related genes using methylation-specific PCR. Complete tumor regression was seen in one patient following administration of sirolimus These tumors display the full range of known EBV latent genes. We describe eight cases of EBV-associated smooth muscle tumors in patients on long-term immunosuppression following renal transplantation in the largest singleinstitution series documented. The mTOR pathway works by integrating various signals such as nutrient availability and growth factors to regulate different processes, including autophagocytosis, protein synthesis, and metabolism
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