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

Department of Surgical Research, Technical University of Dresden, Germany. -dresden-de
Clinical Cancer Research (Impact Factor: 8.72). 10/1999; 5(9):2431-7.
Source: PubMed


The high mutation rate in advanced brain tumors, recent functional studies, and the high frequency of mutations in prostate metastases all strongly suggest that PTEN/MMAC1 alterations are involved in the formation of metastases. We searched for genetic alterations in the PTEN/MMAC1 gene in 56 consecutive brain metastases from various primary tumors by loss of heterozygosity (LOH), direct sequence analysis, and differential PCR analysis. The highest LOH rates were detected in metastases deriving from lung (67%) and breast (64%) cancers. Three (25%) of the eight detected inactivating mutations (one nonsense mutation, one splice-site mutation, one 11-bp deletion, and five homozygous deletions) were found in metastases originating from 12 different lung carcinomas, suggesting that PTEN/MMAC1 alterations may play a role in the progression of this tumor. With the exception of lung carcinomas, our findings indicate that genetic abnormalities of the PTENM/MMAC1 gene are only involved in a relatively small subset of brain metastases. However, the discrepancy between the high overall LOH rate (50%) and the low frequency of PTEN/MMAC1 mutation detection rate (14%) suggests the presence of one or more additional tumor suppressor genes on chromosome 10q.

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    • "One of the most frequently observed genetic alterations in advanced human cancers as detected by loss of heterozygosity (LOH) assays have been found in chromosome 10q23. Extensive studies on this candidate tumor suppressor gene, designated as PTEN, have been validated in a variety of tumors.5 Frequent genetic inactivation of PTEN as detected by LOH occurs in glioblastoma, endometrial cancer, pancreatic cancer, and prostate cancer, and reduced expression has been observed in many other tumor types such as melanoma,6 lung,7,8 and breast cancer.9 "
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