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PTEN/MMAC1 (phosphatase and tensin homolog/mutated in multiple advanced cancers 1) is a tumor suppressor gene, the inactivation of which is an important step in the progression of gliomas to end-stage glioblastoma multiforme. We examined the distribution of PTEN protein in 49 primary human gliomas by immunocytochemistry using polyclonal antibodies that we raised against PTEN-glutathione S-transferase fusion proteins expressed in Escherichia coli. The study group consisted of 6 low-grade astrocytomas, 7 anaplastic astrocytomas, 21 glioblastomas multiforme, 4 low-grade oligodendrogliomas, 6 malignant oligodendrogliomas, and 5 malignant mixed oligoastrocytomas. For each tumor, we determined the percentage of tumor cells showing PTEN immunoreactivity in the most cellular regions of the tumor specimen. In both astrocytomas and oligodendrogliomas, there was an inverse relationship between the percentage of PTEN+ cells and malignancy grade, consistent with a role for PTEN as a tumor suppressor gene, the expression of which declines during glioma progression. In nonneoplastic tissue, PTEN was expressed in human fetal brain at 16, 23, and 27 weeks' gestation, but not in adult brain, indicating that PTEN is developmentally regulated in the CNS. In 21 glioblastomas multiforme, we correlated PTEN protein expression with PTEN gene sequence. Although PTEN-mutant tumors showed significantly diminished PTEN protein expression compared with wild-type cases, suppressed expression of PTEN is more prevalent than predicted from mutation frequencies.