PTEN: One Gene, Many Syndromes

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Abstract
PTEN, on 10q23.3, encodes a major lipid phosphatase which signals down the phosphoinositol‐3‐kinase/Akt pathway and effects G1 cell cycle arrest and apoptosis. Germline PTEN mutations have been found to occur in 80% of classic Cowden syndrome (CS), 60% of Bannayan‐Riley‐Ruvalcaba syndrome (BRRS), up to 20% of Proteus syndrome (PS), and approximately 50% of a Proteus‐like syndrome (PSL). CS is a heritable multiple hamartoma syndrome with a high risk of breast, thyroid, and endometrial carcinomas. BRRS is a congenital autosomal dominant disorder characterized by megencephaly, developmental delay, lipomatosis, and speckled penis. PS and PSL had never been associated with risk of malignancy. Finding germline PTEN mutations in patients with BRRS, PS, and PSL suggests equivalent risks of developing malignancy as in CS with implications for medical management. The mutational spectra of CS and BRRS overlap, with many of the mutations occurring in exons 5, 7, and 8. Genotype–phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5′ of the phosphatase motif were associated with multi‐organ involvement. Pooled analysis of PTEN mutation series of CS and BRRS occurring in the last five years reveals that 65% of CS‐associated mutations occur in the first five exons encoding the phosphatase domain and the promoter region, while 60% of BRRS‐associated mutations occur in the 3′ four exons encoding mainly the C2 domain. Somatic PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors, with the highest frequencies in endometrial carcinomas and glioblastoma multiform. Several mechanisms of PTEN inactivation occur in primary malignancies derived from different tissues, but a favored mechanism appears to occur in a tissue‐specific manner. Inappropriate subcellular compartmentalization and increased/decreased proteosome degradation may be two novel mechanisms of PTEN inactivation. Further functional work could reveal more effective means of molecular‐directed therapy and prevention. Hum Mutat 22:183–198, 2003.