Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity

PTEN/MMAC1 (phosphatase, tensin homologue/mutated in multiple advanced canc ers) is a tumor suppressor protein that has sequence homology with dual-spe cificity phosphatases, which ave capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins, The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinos itol 3,4,5-triphosphate, The PTEN/MMAC1. gene is mutated in the germline! o f patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 g ene in tumors from various tissues, especially endometrium, brain, prostate , and ovary, in which the gene is inactivated very frequently, Germline and somatic mutations in the PTEN/MMAC1 gene occur mostly in the protein codin g region and involve the phosphatase domain and poly(A)(6) stretches. Compa red with germline alterations found in the PTEN/MMAC1 gene, there is a subs tantially increased frequency of frameshift mutations in tumors. Glioblasto mas and endometrial carcinomas appear to have, distinct mutational spectra, probably reflecting differences in the underlying mechanisms of inactivati on of the PTEN/MMAC1 gene in the two tissue types. Also, depending on the t issue type, the gene appears to be involved in the initiation or the progre ssion of cancers. Further understanding of PTEN/MMAC1 gene mutations in dif ferent tumors and the physiologic consequences of these mutations is likely to open up new therapeutic opportunities for targeting this critical gene.