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PTEN loss in the continuum of common cancers, rare syndromes and mouse models

A Corrigendum to this article was published on 12 May 2011

This article has been updated

Key Points

  • PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations. The range of abnormalities in patients with PHTS varies from patient to patient.

  • Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types. These include the classical PHTS-associated tumours like breast, endometrium and thyroid, but also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma.

  • Mouse models of Cowden syndrome, in which a single allele of Pten is deleted or mutated, exhibit characteristic Cowden syndrome phenotypes. Tumour types are very much dependent on the genetic background of the mice suggesting that there may be genetic risk factors for PHTS penetrance in humans.

  • Tissue-specific deletion of Pten in mice can lead to rapid, slow or no tumours, depending on the tissue type. In some cases, tissue-specific Pten deletion can cooperate with other genetic alterations to enhance tumorigenesis. These mouse models have validated mutation or loss of PTEN as an aetiological factor in similar human tumours.

  • PTEN is a lipid phosphatase that acts as a negative regulator of the PI3K–AKT–mTOR pathway, which is an important regulator of cell growth and survival. As such, pharmacological inhibition of this pathway may be exploited for therapy of tumours with altered PTEN, or for tumour prevention in patients with PHTS.

Abstract

PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K–AKT–mTOR pathway1,2. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations3. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.

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Figure 1: Schematic of the PTEN protein.
Figure 2: Canonical PTEN–PI3K–AKT–mTOR pathway.

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Change history

  • 12 May 2011

    In Table 1 on page 293 of this article, all of the references were numbered incorrectly. This has been corrected on both the html and pdf versions.

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Acknowledgements

This Review is dedicated to T.S., a dear patient with Cowden syndrome. The authors remain devoted to the study and cure of Cowden syndrome in her honour and the honour of others who wrestle with the consequences of disease caused by the loss of PTEN.

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Correspondence to Phillip A. Dennis.

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Glossary

Mutation hotspot

A codon that is mutated at a disproportionately high frequency.

Glioma

A type of tumour that originates from glial cells in the brain or spinal cord.

Loss of heterozygosity

Loss of one allele of a gene when the original two alleles can be distinguished. This is common for tumour suppressor genes when the other allele is mutated, although it may occur without mutation of the remaining allele.

Frameshift mutation

Insertion or deletion of nucleotides leading to a change in the protein translation reading frame.

Microsatellite instability

Increased propensity for changes in microsatellite (short repeats within a genome) sequences resulting from defects in DNA repair.

Anaplastic subtype

Undifferentiated thyroid carcinomas that are aggressive, resistant to chemotherapy and radiation, and are almost uniformly lethal.

Goiter

Enlargement of the thyroid gland, which can be due to many factors including iodine deficiency, autoimmune diseases (Graves' disease and Hashimoto's disease), thyroid cancer and genetic syndromes such as Cowden syndrome.

Lhermitte–Duclos

A phenotypic variant of Cowden syndrome in which patients develop dysplastic gangliocytoma of the cerebellum. Adult-onset Lhermitte–Duclos is almost always associated with germline PTEN mutation and is pathognomonic for diagnosing Cowden syndrome.

Glioblastoma

Grade IV high-grade invasive astrocytoma.

Prostatic intraepithelial neoplasia

A non-invasive microscopic lesion in the prostate that may represent a precursor to prostate cancer.

Hypomorphic allele

An allele that is expressed at a lower than usual level.

Xeroderma pigmentosum

A genetic disorder in which patients have decreased DNA repair and a 1,000-fold increased risk of melanoma.

Angiomyolipoma

Benign tumour of the kidney comprised of blood vessels, smooth muscle and adipose tissue that is commonly found in patients with tuberous sclerosis.

Proteus syndrome

A complex, rapidly progressive disorder characterized by mosaicism, hemihypertrophy, congential malformation, tissue overgrowth, subcutaneous tumours and various bone, cutaneous and vascular anomalies.

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Hollander, M., Blumenthal, G. & Dennis, P. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11, 289–301 (2011). https://doi.org/10.1038/nrc3037

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