P07.04 * PROMOTER METHYLATION OF THE LATS1 AND LATS2 GENES IN SCHWANNOMAS

Abstract

Schwannoma is a benign nerve sheath tumor that is typically encapsulated and composed of well-differentiated Schwann cellswhich comprises 5-10% of all intracranial tumors in adults. Approximately 90% of schwannomas are solitary and sporadic, whereas ∼4% are considered to arise in the setting of neurofibromatosis type 2 (NF2) syndrome by NF2 germline mutations. The molecular basis of sporadic schwannomas is not fully understood, other than frequent NF2 mutations (∼60%). LATS1 and the related LATS2 are downstream molecules of NF2 and negative regulators of the YAP oncogene in the Salvador/Warts/Hippo (SWH) signaling pathway. Expression of these genes is reduced due to promoter methylation in a variety of neoplasms including gliomas. In the present study, methylation-specific PCR revealed promoter methylation of the LATS1 and LATS2 in 15 of 91 (16%) and 32 of 91 (35%) schwannomas, respectively. These alterations were significantly more frequent in spinal than in peripheral schwannomas (23% vs 3% for LATS1, P = 0.0171; 42% vs 21% for LATS2, P = 0.0386). LATS1 methylation was also detected in 3 of 4 schwannomatosis cases. Furthermore, neurofibroma / schwannoma hybrid tumors showed promoter methylation in LATS1 (3/14; 21%) and LATS2 (8/14; 57%). LATS1 and LATS2 promoter methylation were largely mutually exclusive, and there was a significant negative correlation (P = 0.003); only 10 cases had methylation in both genes. These results suggest that LATS1 and LATS2 promoter methylation may be additional molecular mechanisms resulting in an abnormal SWH pathway in schwannomas and related tumors.