Expression of EBV latent antigens, mammalian target of rapamycin, and tumor suppression genes in EBV-positive smooth muscle tumors: clinical and therapeutic implications.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ong
Kong Wee
KW
Department of Surgical Oncology, National Cancer Centre, Singapore. Ong.Kong.Wee@nccs.com.sg
Teo
Marissa
M
Lee
Victor
V
Ong
Danny
D
Lee
Ann
A
Tan
Chieh Suai
CS
Vathsala
A
A
Toh
Han Chong
HC
D000328:Adult; D000956:Antigens, Viral / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005260:Female; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D018235:Smooth Muscle Tumor / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C082925:retinoic acid receptor beta; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases