PTEN: One Gene, Many Syndromes

By C. Eng. Human Mutation, 2003

804 citations recorded by the source corpus.

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. © 2003 Wiley‐Liss, Inc.

View Paper: https://www.semanticscholar.org/paper/be416969b7ea182483f0f62bae3b2cfd888b03d8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

1. David M. Sabatini
2. Arkaitz Carracedo
3. P. Pandolfi
4. D. Guertin
5. N. Chalhoub
6. L. Trotman
7. D. Altomare
8. B. Carver

Citations in the corpus

• Automated inference of molecular mechanisms of disease from amino acid substitutions (2009, background): “Exon 5, which encodes the phosphatase core motif, accounts for 40% all PTEN mutations (Eng, 2003) and includes catalytic residues C124 and D92 (Lee et al., 1999).”
• Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis (2006, background): “Numerous types of tumours, both sporadic and those that arise as a component of a cancer predisposition syndrome, show alterations in PTEN”
• PTEN and the PI3-kinase pathway in cancer. (2009, background): “Inherited mutations in PTEN are associated with a wide and diverse clinical spectrum of disorders, collectively known as PTEN hamartoma tumor syndromes, that are characterized by the development of benign tumors (hamartomas) (9,54).”
• The PTEN–PI3K pathway: of feedbacks and cross-talks (2008, background): “For example, PTEN is commonly mutated in its phosphatase domain (Eng, 2003); and in glioblastoma, mutations that impair its proper membrane localization might result in deficient tumor-suppressive activity (Walker et al.”
• Defining the role of mTOR in cancer. (2007, background): “Like tsc1 and tsc2, the tumor suppressor genes linked to these diseases (pten, lkb1, nf1, and flcn respectively) encode proteins that restrict mTORC1 signaling (Baba et al., 2006; Corradetti et al., 2004; Eng, 2003; Johannessen et al., 2005; Shaw et al., 2004).”
• ERBB receptors and cancer: the complexity of targeted inhibitors (2005, background): “In this respect, constitutive PI3K–AKT signalling through loss of PTEN expressio”
• Ubiquitination regulates PTEN nuclear import and tumor suppression. (2007, background): “Specifically, germline mutation of PTEN has been shown to underlie the closely related autosomal dominant tumor susceptibility syndromes Cowden disease and Bannayan-Riley-Ruvalcaba syndrome (Eng, 2003).”