PTEN hamartoma tumor syndrome: An overview

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 09/2009; 11(10):687-94. DOI: 10.1097/GIM.0b013e3181ac9aea
Source: PubMed


PTEN hamartoma tumor syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumor suppressor PTEN. These allelic disorders, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are associated with unregulated cellular proliferation leading to the formation of hamartomas. Thus far, an increased risk of malignancy has only been documented in Cowden syndrome; however, current recommendations advise that all individuals with PTEN hamartoma tumor syndrome follow the cancer surveillance strategies suggested for Cowden syndrome until further data indicate otherwise. Because any individual phenotypic feature of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are frequently present in the general population, many individuals often go undiagnosed and consequently do not benefit from available cancer surveillance strategies. Therefore, it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose and provide preventative care. This overview details the clinical description of the PTEN hamartoma tumor syndrome and associated disorders, their diagnosis and molecular/genetic testing, as well as differential diagnosis for assessment of other hamartoma-associated syndromes.

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Available from: Charis Eng, May 19, 2014
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    • "PTEN is also a known negative regulator of genes associated with ISC self-renewal and maintenance, including mTert (telomerase reverse transcriptase) (Kang et al., 1999;Kyo and Inoue, 2002;You et al., 2007;Zhou et al., 2006). In the intestine, PTEN is an important regulator of homeostasis (Langlois et al., 2009)with loss-of-function mutations giving rise to the PTEN hamartoma tumor syndrome (Hobert and Eng, 2009). In addition, PTEN is negatively regulated by phosphorylation (Ross and Gericke, 2009;Vazquez et al., 2000Vazquez et al., , 2001), and both PTEN and its inactive isoform, phospho-PTEN (pPTEN), have been shown to mark a discrete population of DNA label-retaining cells in the +4 crypt position (He et al., 2004). "
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    ABSTRACT: The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress. Richmond et al. show that PTEN is required for dormant intestinal stem cell (d-ISC) maintenance and regeneration after intestinal injury. Changes in nutrient status (fasting) lead to transient PTEN inhibition, rendering d-ISCs functionally poised to contribute to regeneration upon re-feeding via cell-autonomous activation of the insulin/growth factor→PI3K→AKT→mTORC1 pathway.
    Full-text · Article · Dec 2015 · Cell Reports
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    • "Germline and somatic PTEN mutations are found frequently in human cancer (Chalhoub and Baker, 2009; Hobert and Eng, 2009). Despite the important role PTEN plays in antagonizing the PI3K-AKT pathway in the cytoplasm (Chen et al., 2006; Stambolic et al., 1998), emerging evidence argues that nuclear PTEN participates in multiple anti-cancer processes and, in particular, participates in maintenance of genomic integrity to suppress tumorigenesis (Bassi et al., 2013; Chen et al., 2014; Shen et al., 2007; Song et al., 2011; Sun et al., 2014). "
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    ABSTRACT: PTEN is a tumor suppressor frequently mutated in human cancers. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)-AKT cascade, and nuclear PTEN guards the genome by multiple mechanisms. Here, we report that PTEN physically associates with the minichromosome maintenance complex component 2 (MCM2), which is essential for DNA replication. Specifically, PTEN dephosphorylates MCM2 at serine 41 (S41) and restricts replication fork progression under replicative stress. PTEN disruption results in unrestrained fork progression upon replication stalling, which is similar to the phenotype of cells expressing the phosphomimic MCM2 mutant S41D. Moreover, PTEN is necessary for prevention of chromosomal aberrations under replication stress. This study demonstrates that PTEN regulates DNA replication through MCM2 and loss of PTEN function leads to replication defects and genomic instability. We propose that PTEN plays a critical role in maintaining genetic stability through a replication-specific mechanism, and this is a crucial facet of PTEN tumor suppressor activity.
    Full-text · Article · Nov 2015 · Cell Reports
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    • "Among other possible overgrowth candidate genes, germ-line mutations in the PTEN gene have been previously associated with a group of disorders called PTEN hamartoma tumor syndrome, which are characterized by macrocephaly, intellectual disability and overgrowth [Yin and Shen, 2008; Hobert and Eng, 2009; Tan et al., 2011]. They include Cowden syndrome [OMIM 158350; Tan et al., 2011], with 85% of patients carrying a PTEN mutation; Bannayan-Riley-Ruvalcaba syndrome, with 65% of patients with PTEN mutation, and Proteus syndrome (OMIM 176920), with 20% of patients with a mutation in the PTEN gene [Zhou et al., 2001, Eng, 2003; Orloff and Eng, 2008]. "
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    ABSTRACT: Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).
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