Genetic alterations of the tumor suppressor gene PTEN/MMAC1 in human brainmetastases

The high mutation rate in advanced brain tumors, recent functional studies, and the high frequency of mutations in prostate metastases all strongly su ggest that PTEN/MMAC1 alterations are involved in the formation of metastas es, We searched for genetic alterations in the PTEN/MMAC1 gene in 56 consec utive brain metastases from various primary tumors by loss of heterozygosit y (LOH), direct sequence analysis, and differential PCR analysis. The highe st LOH rates were detected in metastases deriving from lung (67%) and breas t (64%) cancers. Three (25%) of the eight detected inactivating mutations ( one nonsense mutation, one splice-site mutation, one Il-bp deletion, and fi ve homozygous deletions) were found in metastases originating from 12 diffe rent lung carcinomas, suggesting that PTEN/MMAC1 alterations may play a rol e in the progression of this tumor, With the exception of lung carcinomas, our findings indicate that genetic abnormalities of the PTENM/MMAC1 gene ar e only involved in a relatively small subset of brain metastases, However, the discrepancy between the high overall LOH rate (50%) and the low frequen cy of PTEN/MMAC1 mutation detection rate (14%) suggests the presence of one or more additional tumor suppressor genes on chromosome 10q.