MMAC1 PTEN MUTATIONS IN PRIMARY TUMOR SPECIMENS AND TUMOR-CELL LINES/

A candidate tumor suppressor gene, MMAC1/PTEN, located in human chromo some band 10q23, was recently identified based on sequence alterations observed in several glioma, breast, prostate, and kidney tumor specim ens or cell lines. To further investigate the mutational profile of th is gene in human cancers, we examined a large set of human tumor speci mens and cancer cell lines of many types for 10q23 allelic losses and MMAC1 sequence alterations. Loss of heterozygosity (LOH) at the MMAC1 locus was observed in approximately one-half of the samples examined, consistent with the high frequency of 10q allelic loss reported for ma ny cancers. Of 124 tumor specimens exhibiting LOH that have been scree ned for MMAC1 alterations to date, we have detected variants in 13 (si milar to 10%) of these primary tumors; the highest frequency of varian ts was found in glioblastoma specimens (similar to 23%). Novel alterat ions identified in this gene include a missense variant in a melanoma sample and a splicing variant and a nonsense mutation in pediatric gli oblastomas. Of 76 tumor cell lines prescreened for probable LOH, micro sequence alterations of MMAC1 were detected in 12 (similar to 16%) of the lines, including those derived from astrocytoma, leukemia, and mel anoma tumors, as well as bladder, breast, lung, prostate, submaxillary gland, and testis carcinomas. In addition, in this set of tumor cell lines, we detected 11 (similar to 14%) homozygous deletions that elimi nated coding portions of MMAC1, a class of abnormality not detected by our methods in primary tumors. These data support the occurrence of i nactivating MMAC1 alterations in multiple human cancer types. In addit ion, we report the discovery of a putative pseudogene of MMAC1 localiz ed on chromosome 9.