PTEN; phosphatase and tensin homolog (10q23.3)

Gene Summary

Gene:PTEN; phosphatase and tensin homolog
Aliases: BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del
Summary:This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
Updated:21 December, 2014


What does this gene/protein do?
Show (202)


What pathways are this gene/protein implicaed in?
- mTOR Signaling Pathway BIOCARTA
- mTOR Signaling Pathway BIOCARTA
- PTEN dependent cell cycle arrest and apoptosis BIOCARTA
- PTEN dependent cell cycle arrest and apoptosis BIOCARTA
- Regulation of eIF4e and p70 S6 Kinase BIOCARTA
- Regulation of eIF4e and p70 S6 Kinase BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway BIOCARTA
- Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway BIOCARTA
- Focal adhesion KEGG
- Focal adhesion KEGG
- Inositol phosphate metabolism KEGG
- Inositol phosphate metabolism KEGG
- Phosphatidylinositol signaling system KEGG
- Phosphatidylinositol signaling system KEGG
- Tight junction KEGG
- Tight junction KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

As tumours progress to more advanced stages, they tend to acquire an increasing number of genetic alterations. One common alteration seen in a range of different advanced cancers is mutation of the PTEN gene, a gene which is linked with cell regulation and apoptosis (programmed cell death). Mutations in the PTEN gene are documented in cancers of the breast, prostate, endometrium, ovary, colon, melanoma, glioblastoma. and lymphoma. Animal models have shown that the loss of just one copy of the PTEN gene is enough to interrupt cell signalling and begin the process of uncontrolled cell growth. However, the significance of PTEN alterations in carcinogenesis is controversial since aberrant transcripts of PTEN have also been identified in normal non-cancerous tissues.

Research Indicators

Publications Per Year (1989-2014)
Graph generated 21 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 21 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (16)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Endometrial CancerPTEN mutations in Endometrial Cancer
Mutations of the PTEN suppressor gene are the most frequent genetic abnormality in endometrial cancers. They occur in 40-80% of endometrioid carcinomas, which account for the majority of endometrial cancers. PTEN mutations have also been detected in the precancerous condition endometrial intraepithelial neoplasia.
View Publications424
Breast CancerPTEN and Breast Cancer View Publications399
Brain and CNS TumoursPTEN and Glioblastoma View Publications372
Astrocytoma, ChildhoodPTEN and Astrocytoma View Publications371
Prostate CancerPTEN and Prostate Cancer View Publications369
Lung CancerPTEN and Lung Cancer View Publications282
Cowden SyndromePTEN mutations in Cowdon Syndrome
Cowdon Syndrome is a hereditary disease characterised by multiple ectodermal, mesodermal, and endodermal nevoid abnormalities. People with the syndrome have an elevated risk of breast cancer, thyroid cancer and endometrial cancer.
View Publications261
Thyroid CancerPTEN and Thyroid Cancer View Publications112
Skin CancerPTEN and Skin Cancer View Publications85
Stomach CancerPTEN and Stomach Cancer View Publications70
Soft Tissue SarcomaPTEN and Soft Tissue Sarcoma View Publications54
-PTEN in Precancerous Conditions
PTEN mutations are implicated in a number of precancerous conditions. For example Mutter and colleagues (JNCI, 2000) found 16/29 (55%) of endometrial intraepithelial neoplasia (a precancerous condition) had PTEN mutations compared to 25/30 (83%) of endometrioid adenocarcinomas. They suggest that PTEN may be a useful immunohistochemical biomarker for premalignant disease. The precancers were characterised by mutation of only 1 PTEN allele while the adenocarcinomas showed reduced or complete loss of PTEN protein expression.
View Publications53
MesotheliomaPTEN expression in Mesothelioma View Publications17
Salivary Gland CancerPTEN and Salivary Gland Cancer View Publications15
Testicular CancerPTEN and Testicular Cancer View Publications10
Ewing's SarcomaPTEN Amplification in Ewing's Sarcoma?
In a genome-wide copy-number analysis of Ewing's sarcoma, Lynn et al (2013) found localized copy-number alterations of PTEN.
View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: PTEN (cancer-related)

Chen ZX, Sang QT, Du YG, Xin YY
Silence of PTEN in colorectal cancer cells via siRNA inhibits cell growth.
J Environ Pathol Toxicol Oncol. 2014; 33(3):233-7 [PubMed] Related Publications
Colorectal cancer is one of the most commonly diagnosed cancers and is a leading cause of cancerrelated death worldwide. In this study, we aimed to examine the expression of PTEN in human colorectal cancer cell lines HCT-8 and to further investigate the functions of PTEN in colorectal cancer cells. Therefore, we established stably transfected HCT-8 cell lines expressing siRNA targeting the PTEN gene. Cell proliferation and cell migration of the siPTEN cells were characterized by the CCK-8 assay and the Transwell assay, respectively. Our results show that constitutive knockdown of the PTEN gene in siPTEN cells significantly promoted cell proliferation and migration. These results suggest that PTEN may play important roles in colorectal cancer cell proliferation and migration.

Related: Colorectal (Bowel) Cancer

Xue W, Chen S, Yin H, et al.
CRISPR-mediated direct mutation of cancer genes in the mouse liver.
Nature. 2014; 514(7522):380-4 [PubMed] Article available free on PMC after 16/04/2015 Related Publications
The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem cells. Here we describe a new method of cancer model generation using the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system in vivo in wild-type mice. We used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) to the liver that directly target the tumour suppressor genes Pten (ref. 5) and p53 (also known as TP53 and Trp53) (ref. 6), alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology. Simultaneous targeting of Pten and p53 induced liver tumours that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumour tissue revealed insertion or deletion mutations of the tumour suppressor genes, including bi-allelic mutations of both Pten and p53 in tumours. Furthermore, co-injection of Cas9 plasmids harbouring sgRNAs targeting the β-catenin gene and a single-stranded DNA oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-catenin. This study demonstrates the feasibility of direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.

Related: Liver Cancer AKT1 CTNNB1 gene

Ozawa T, Riester M, Cheng YK, et al.
Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma.
Cancer Cell. 2014; 26(2):288-300 [PubMed] Article available free on PMC after 11/08/2015 Related Publications
To understand the relationships between the non-GCIMP glioblastoma (GBM) subgroups, we performed mathematical modeling to predict the temporal sequence of driver events during tumorigenesis. The most common order of evolutionary events is 1) chromosome (chr) 7 gain and chr10 loss, followed by 2) CDKN2A loss and/or TP53 mutation, and 3) alterations canonical for specific subtypes. We then developed a computational methodology to identify drivers of broad copy number changes, identifying PDGFA (chr7) and PTEN (chr10) as driving initial nondisjunction events. These predictions were validated using mouse modeling, showing that PDGFA is sufficient to induce proneural-like gliomas and that additional NF1 loss converts proneural to the mesenchymal subtype. Our findings suggest that most non-GCIMP mesenchymal GBMs arise as, and evolve from, a proneural-like precursor.

Related: Chromosome 10 Chromosome 7 PDGFB gene PDGFRA gene EGFR

Lázaro-Ibáñez E, Sanz-Garcia A, Visakorpi T, et al.
Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes.
Prostate. 2014; 74(14):1379-90 [PubMed] Related Publications
BACKGROUND: Extracellular vesicles (EVs) are cell-derived membrane vesicles. EVs contain several RNAs such as mRNA, microRNAs, and ncRNAs, but less is known of their genomic DNA (gDNA) content. It is also unknown whether the DNA cargo is randomly sorted or if it is systematically packed into specific EV subpopulations. The aim of this study was to analyze whether different prostate cancer (PCa) cell-derived EV subpopulations (apoptotic bodies, microvesicles, and exosomes) carry different gDNA fragments.
METHODS: EV subpopulations were isolated from three PCa cell lines (LNCaP, PC-3, and RC92a/hTERT) and the plasma of PCa patients and healthy donors, and characterized by transmission electron microscopy, nanoparticle tracking analysis and total protein content. gDNA fragments of different genes were detected by real time quantitative PCR and confirmed by DNA sequencing.
RESULTS: We report that the concentration of EVs was higher in the cancer patients than in the healthy controls. EV subpopulations differed from each other in terms of total protein and DNA content. Analysis of gDNA fragments of MLH1, PTEN, and TP53 genes from the PCa cell-derived EV subpopulations showed that different EVs carried different gDNA content, which could even harbor specific mutations. Altogether, these results suggest that both nucleic acids and proteins are selectively and cell-dependently packed into the EV subtypes.
CONCLUSIONS: EVs derived from PCa cell lines and human plasma samples contain double-stranded gDNA fragments which could be used to detect specific mutations, making EVs potential biomarkers for cancer diagnostics and prognostics.

Related: Apoptosis Prostate Cancer

Xue M, Yao S, Hu M, et al.
HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway.
Nucleic Acids Res. 2014; 42(15):9862-79 [PubMed] Article available free on PMC after 11/08/2015 Related Publications
Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV). Although the interaction between HIV-1 and KSHV plays a pivotal role in promoting the aggressive manifestations of KS, the pathogenesis underlying AIDS-KS remains largely unknown. Here we examined HIV-1 Nef protein promotion of KSHV oncoprotein K1-induced angiogenesis. We showed that both internalized and ectopic expression of Nef in endothelial cells synergized with K1 to facilitate vascular tube formation and cell proliferation, and enhance angiogenesis in a chicken CAM model. In vivo experiments further indicated that Nef accelerated K1-induced angiogenesis and tumorigenesis in athymic nu/nu mice. Mechanistic studies revealed that Nef and K1 synergistically activated PI3K/AKT/mTOR signaling by downregulating PTEN. Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3' UTR of its mRNA. Inhibition of miR-718 expression increased PTEN synthesis and suppressed the synergistic effect of Nef- and K1-induced angiogenesis and tumorigenesis. These results indicate that, by targeting PTEN, miR-718 mediates Nef- and K1-induced angiogenesis via activation of AKT/mTOR signaling. Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target.

Related: AKT1 Signal Transduction

Yang AY, Lee JH, Shu L, et al.
Genome-wide analysis of DNA methylation in UVB- and DMBA/TPA-induced mouse skin cancer models.
Life Sci. 2014; 113(1-2):45-54 [PubMed] Related Publications
AIMS: Ultraviolet irradiation and carcinogens have been reported to induce epigenetic alterations, which potentially contribute to the development of skin cancer. We aimed to study the genome-wide DNA methylation profiles of skin cancers induced by ultraviolet B (UVB) irradiation and 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-1,3-acetate (TPA).
MAIN METHODS: Methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing was utilized to ascertain the DNA methylation profiles in the following common mouse skin cancer models: SKH-1 mice treated with UVB irradiation and CD-1 mice treated with DMBA/TPA. Ingenuity® Pathway Analysis (IPA) software was utilized to analyze the data and to identify gene interactions among the different pathways.
KEY FINDINGS: 6003 genes in the UVB group and 5424 genes in the DMBA/TPA group exhibited a greater than 2-fold change in CpG methylation as mapped by the IPA software. The top canonical pathways identified by IPA after the two treatments were ranked were pathways related to cancer development, cAMP-mediated signaling, G protein-coupled receptor signaling and PTEN signaling associated with UVB treatment, whereas protein kinase A signaling and xenobiotic metabolism signaling were associated with DMBA/TPA treatment. In addition, the mapped IL-6-related inflammatory pathways displayed alterations in the methylation profiles of inflammation-related genes linked to UVB treatment.
SIGNIFICANCE: Genes with altered methylation were ranked in the UVB and DMBA/TPA models, and the molecular interaction networks of those genes were identified by the IPA software. The genome-wide DNA methylation profiles of skin cancers induced by UV irradiation or by DMBA/TPA will be useful for future studies on epigenetic gene regulation in skin carcinogenesis.

Related: Signal Transduction Skin Cancer

Bailón E, Ugarte-Berzal E, Amigo-Jiménez I, et al.
Overexpression of progelatinase B/proMMP-9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen.
J Leukoc Biol. 2014; 96(2):185-99 [PubMed] Related Publications
This study addresses the role of (pro)MMP-9 overexpression in CLL cell migration. We have used primary CLL cells and CLL-derived MEC-1 cells transfected with empty (mock cells) or proMMP-9-encoding (MMP-9 cells) lentiviral vectors. The constitutive (pro)MMP-9 expression in mock cells and primary CLL cells was similar, whereas in MMP-9 cells, expression resembled that of CLL cells incubated with proMMP-9. In xenograft models, in NOD/SCID mice, MMP-9-MEC-1 transfectants showed significantly reduced homing to bone marrow and spleen compared with mock cells. Likewise, incubation of primary CLL cells with proMMP-9, before injection into mice, inhibited their homing to these organs. This inhibition was specific, dose-dependent, and observed in all CLL tested, independently of prognostic markers or disease stage. Additionally, the MMP-9 catalytic activity was only partially involved, as the inactive mutant proMMP-9MutE had a partial effect. MMP-9 cells also showed impaired migration in vitro, which was reverted by reducing (pro)MMP-9 expression with siRNAs. CLL migration thus requires optimal (pro)MMP-9 expression levels, below or above which migration is hampered. Biochemical analysis of the (pro)MMP-9 effect indicated that MMP-9 cells or primary CLL cells incubated with proMMP-9 had reduced activation of migration regulatory molecules, including RhoAGTPase, Akt, ERK, and FAK. In contrast, p190RhoGAP (RhoA inhibitor) and PTEN (Akt/ERK/FAK inhibitor) were up-regulated in MMP-9 cells. Reduction of (pro)MMP-9 expression by siRNAs restored RhoA activity and diminished PTEN levels. Our results reveal a novel function for (pro)MMP-9 in modulating signaling pathways leading to CLL cell arrest. Therefore, local high (pro)MMP-9 expression may contribute to malignant cell retention in lymphoid organs and disease progression.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology MMP9: matrix metallopeptidase 9 AKT1 Signal Transduction

Li Z, Li J, Bi P, et al.
Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state.
Mol Cell Biol. 2014; 34(19):3642-61 [PubMed] Article available free on PMC after 11/08/2015 Related Publications
One outcome of activation of the phosphatidylinositol 3-kinase (PI3K) pathway is increased aerobic glycolysis, but the upstream signaling events that regulate the PI3K pathway, and thus the Warburg effect, are elusive. Increasing evidence suggests that Plk1, a cell cycle regulator, is also involved in cellular events in addition to mitosis. To test whether Plk1 contributes to activation of the PI3K pathway, and thus aerobic glycolysis, we examined potential targets of Plk1 and identified PTEN as a Plk1 substrate. We hypothesize that Plk1 phosphorylation of PTEN leads to its inactivation, activation of the PI3K pathway, and the Warburg effect. Our data show that overexpression of Plk1 leads to activation of the PI3K pathway and enhanced aerobic glycolysis. In contrast, inhibition of Plk1 causes markedly reduced glucose metabolism in mice. Mechanistically, we show that Plk1 phosphorylation of PTEN and Nedd4-1, an E3 ubiquitin ligase of PTEN, results in PTEN inactivation. Finally, we show that Plk1 phosphorylation of PTEN promotes tumorigenesis in both its phosphatase-dependent and -independent pathways, revealing potentially new drug targets to arrest tumor cell growth.

Related: Signal Transduction

Mason JM, Lin DC, Wei X, et al.
Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent.
Cancer Cell. 2014; 26(2):163-76 [PubMed] Related Publications
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.

Related: Breast Cancer

Ryzhova MV, Shishkina LV, Zheludkova OG, et al.
[Comparative characteristics of genetic aberrations in glioblastomas in children and adults].
Zh Vopr Neirokhir Im N N Burdenko. 2014; 78(2):3-11; discussion 11 [PubMed] Related Publications
Glioblastomas in children and adults are a heterogeneous group of tumors that can be divided into at least three different subgroups: pediatric glioblastomas, IDH1-mutant glioblastomas in adults (the most favorable prognostic subtype), and IDH1-wild type glioblastomas in adults. According to the frequency of detected cytogenetic aberrations (amplification of the MYC/MYCN, EGFR and PDGRFA oncogenes, homozygous deletion of the CDKN2A gene, and deletion of the PTEN gene), pediatric glioblastomas bear analogy to the subgroup of IDH1-mutant glioblastomas in adults.

Wei B, Wang L, Zhao X, et al.
Co-mutated pathways analysis highlights the coordination mechanism in glioblastoma multiforme.
Neoplasma. 2014; 61(4):424-32 [PubMed] Related Publications
The mutation of cancer represents a high heterogeneity characteristic, setting a big obstacle in the mechanism study of it. In this study, we explored the distributions of mutated genes in pathways in glioblastoma multiforme (GBM), and constructed networks of co-mutated pathway pairs under the false discovery rate (FDR) control. By comparing the mutation frequencies, a total of 50 mutated genes were screened with the frequency > 3, and TP53, PTEN, and EGFR were the top 3 genes. By KEGG enrichment, 18 pathways of the mutation gene spectrum of GBM were enriched. These pathways were further studied to explore the coordination between pathways, co-mutated pathway pairs, such as mismatch repair/vascular smooth muscle contraction, mismatch repair/long-term depression, mismatch repair/dopaminergic synapse, and TGF-beta signaling pathway/retrograde endocannabinoid signaling pathway were enriched in the network under FDR < 0.01; and cell cycle/p53 signaling was a co-mutated pathway pairs in the network under FDR < 0.05. Meanwhile, the samples overlap levels of enriched pathways were calculated for further confirming of the co-mutated pathway model. By the co-mutated pathway analysis, the coordination mechanism of cancer can be explored, and it may provide basis for the pathogenesis and combined therapy study of cancer.

Related: Signal Transduction

Goschzik T, Gessi M, Denkhaus D, Pietsch T
PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region.
J Neuropathol Exp Neurol. 2014; 73(8):747-51 [PubMed] Related Publications
Papillary tumors of the pineal region (PTPR) are recognized as a distinct entity in the World Health Organization classification of CNS tumors. Papillary tumors of the pineal region frequently show loss of chromosome 10, but no studies have investigated possible target genes on this chromosome. Chromosome 10 harbors the PTEN (phosphatase and tensin homolog) gene, the inactivation of which, by mutation or epigenetic silencing, has been observed in different brain tumors, including high-grade gliomas. In this study, we investigated copy number changes by molecular inversion probe (MIP) analysis and the mutational status of PTEN in 13 PTPR by direct sequencing. MIP analysis of 5 PTPR showed chromosome 10 loss in all cases. In addition, there were losses of chromosomes 3, 14, 22, and X, and gains of whole chromosomes 8, 9, and 12 in more than 1 case. One case had a homozygous PTEN deletion; and 2 point mutations in exon 7 of PTEN (G251D and Q261stop) were found. Immunohistochemistry revealed decrease or loss of the PTEN protein and increased expression of p-Akt and p-S6. These results indicated that PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway may play a role in the biology of PTPR. This evidence may lead to the possible use of PI3K/Akt/mTOR inhibitors in therapy for patients with PTPR.

Related: MUC1 gene Signal Transduction

Chen D, Goswami CP, Burnett RM, et al.
Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.
Cancer Res. 2014; 74(16):4270-81 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Circulating microRNAs (miRNA) are emerging as important biomarkers of various diseases, including cancer. Intriguingly, circulating levels of several miRNAs are lower in patients with cancer compared with healthy individuals. In this study, we tested the hypothesis that a circulating miRNA might serve as a surrogate of the effects of cancer on miRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR486 is lower in patients with breast cancer compared with healthy individuals and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR486 were relatively reduced in muscle, where there was elevated expression of the miR486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD, which controls miR486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro were sufficient to elicit reduced levels of miR486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated tumor necrosis factor α (TNFα) and four additional cytokines as mediators of miR486 expression in CM-treated cells. Because miR486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.

Related: Breast Cancer Signal Transduction

Gong C, Nie Y, Qu S, et al.
miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors.
Cancer Res. 2014; 74(16):4341-52 [PubMed] Related Publications
Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA-positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21.

Related: Breast Cancer SMAD7 miR-21

Ross JS, Wang K, Elkadi OR, et al.
Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer.
J Clin Pathol. 2014; 67(9):772-6 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
AIMS: Small cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only ∼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice.
METHODS: DNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations.
RESULTS: A total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 1–10). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%).
CONCLUSIONS: Greater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.

Related: Lung Cancer Small Cell Lung Cancer

Seok JK, Lee SH, Kim MJ, Lee YM
MicroRNA-382 induced by HIF-1α is an angiogenic miR targeting the tumor suppressor phosphatase and tensin homolog.
Nucleic Acids Res. 2014; 42(12):8062-72 [PubMed] Article available free on PMC after 15/08/2015 Related Publications
Recent studies have revealed that microRNAs (miRs) play important roles in the regulation of angiogenesis. In this study, we have characterized miR-382 upregulation by hypoxia and the functional relevance of miR-382 in tumor angiogenesis. miRs induced by hypoxia in MKN1 human gastric cancer cells were investigated using miRNA microarrays. We selected miR-382 and found that the expression of miR-382 was regulated by HIF-1α. Conditioned media (CM) from MKN1 cells transfected with a miR-382 inhibitor (antagomiR-382) under hypoxic conditions significantly decreased vascular endothelial cell (EC) proliferation, migration and tube formation. Algorithmic programs (Target Scan, miRanda and cbio) predicted that phosphatase and tensin homolog (PTEN) is a target gene of miR-382. Deletion of miR382-binding sequences in the PTEN mRNA 3'-untranslated region (UTR) diminished the luciferase reporter activity. Subsequent study showed that the overexpression of miR-382 or antagomiR-382 down- or upregulated PTEN and its downstream target AKT/mTOR signaling pathway, indicating that PTEN is a functional target gene of miR-382. In addition, PTEN inhibited miR-382-induced in vitro and in vivo angiogenesis as well as VEGF secretion, and the inhibition of miR-382 expression reduced xenograft tumor growth and microvessel density in tumors. Taken together, these results suggest that miR-382 induced by hypoxia promotes angiogenesis and acts as an angiogenic oncogene by repressing PTEN.

Related: HIF1A Angiogenesis and Cancer AKT1 Stomach Cancer Gastric Cancer

Jour G, Scarborough JD, Jones RL, et al.
Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics.
Hum Pathol. 2014; 45(8):1563-71 [PubMed] Related Publications
Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases. MAP2K4, AURKA, AURKB, and c-MYC amplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of the TP53 (24%), PTEN (16%), and CDKN2A (20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, including RB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1, and FLT4 genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.

Related: Soft Tissue Sarcomas

Mendes RD, Sarmento LM, Canté-Barrett K, et al.
PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events.
Blood. 2014; 124(4):567-78 [PubMed] Related Publications
Phosphatase and tensin homolog (PTEN)-inactivating mutations and/or deletions are an independent risk factor for relapse of T-cell acute lymphoblastic leukemia (T-ALL) patients treated on Dutch Childhood Oncology Group or German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia protocols. Some monoallelic mutated or PTEN wild-type patients lack PTEN protein, implying that additional PTEN inactivation mechanisms exist. We show that PTEN is inactivated by small deletions affecting a few exons in 8% of pediatric T-ALL patients. These microdeletions were clonal in 3% and subclonal in 5% of patients. Conserved deletion breakpoints are flanked by cryptic recombination signal sequences (cRSSs) and frequently have non-template-derived nucleotides inserted in between breakpoints, pointing to an illegitimate RAG recombination-driven activity. Identified cRSSs drive RAG-dependent recombination in a reporter system as efficiently as bona fide RSSs that flank gene segments of the T-cell receptor locus. Remarkably, equivalent microdeletions were detected in thymocytes of healthy individuals. Microdeletions strongly associate with the TALLMO subtype characterized by TAL1 or LMO2 rearrangements. Primary and secondary xenotransplantation of TAL1-rearranged leukemia allowed development of leukemic subclones with newly acquired PTEN microdeletions. Ongoing RAG activity may therefore actively contribute to the acquisition of preleukemic hits, clonal diversification, and disease progression.

Related: LMO2 gene TAL1 gene

Guan B, Rahmanto YS, Wu RC, et al.
Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis.
J Natl Cancer Inst. 2014; 106(7) [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The chromatin remodeling gene, ARID1A, has been implied as a tumor suppressor, and its somatic inactivating mutations occur in a wide variety of human cancers, most frequently in ovarian and uterine endometrioid and ovarian clear cell carcinomas. Tumors with ARID1A mutations also frequently harbor PTEN or PIK3CA mutations, suggesting their collaboration in tumorigenesis. Here, we used a conditional knockout mouse model in which Arid1a and Pten were deleted either individually or in combination in the mouse ovarian surface epithelium. After 6 months, 59.1% of mice with Arid1a and Pten double knockout developed ovarian endometrioid or undifferentiated carcinoma, whereas the remaining mice showed hyperplasia of ovarian surface epithelium. In contrast, 52 mice with homozygous or heterozygous deletion in either Arid1a or Pten did not develop ovarian lesions. These results demonstrate that inactivation of Arid1a alone is insufficient for tumor initiation but it requires additional genetic alteration(s) such as Pten deletion to drive tumorigenesis.

Related: Ovarian Cancer

Silva FC, Lisboa BC, Figueiredo MC, et al.
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.
BMC Med Genet. 2014; 15:55 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Germ line mutations in BRCA1 and BRCA2 (BRCA1/2) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of BRCA1/2, TP53 R337H, CHEK2 1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes (PTEN, ATM, NBN, RAD50, RAD51, BRIP1, PALB2, MLH1, MSH2, MSH6, TP53, CDKN2A, CDH1 and CTNNB1).
METHODS: Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the BRCA1 and BRCA2 genes; capillary sequencing was used for point mutation for both variants TP53 R337H and CHEK2 1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.
RESULTS: The positive detection rate in our series was 26%. BRCA1 pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas BRCA2 mutations were found in 7 cases. We also found three patients with the TP53 R337H mutation and one patient with the CHEK2 1100delC mutation. Seven (25%) pathogenic mutations in BRCA1/2 were firstly described, including a splice-site BRCA1 mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in ATM and exon 2 in PTEN were identified in BRCA2-mutated and BRCA1/2-negative patients, respectively.
CONCLUSIONS: In summary, our results showed a high frequency of BRCA1/2 mutations and a higher prevalence of BRCA1 (64.5%) gene. Moreover, the detection of the TP53 R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for BRCA1/2 genes should be tested for the TP53 R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with BRCA2 point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.


Im E, Jung J, Pothoulakis C, Rhee SH
Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10(-/-) mice.
Gastroenterology. 2014; 147(3):667-679.e10 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND & AIMS: Early-onset ulcerative colitis, which is considered severe colonic inflammation that develops in infants and young children, can be caused by alterations in interleukin (IL)-10 signaling, although other factors are involved in its pathogenesis. We investigated whether loss of phosphatase and tensin homologue (PTEN), which regulates many important cell functions such as cell proliferation, cell survival, and Toll-like receptor (TLR) signaling pathways, contributes to the development of colitis in Il10(-/-) mice.
METHODS: We generated Il10(-/-) mice (in C57BL/6 and C3H/HeJBir background strains) with disruption of Pten in the intestinal epithelium (Ints(ΔPten/ΔPten);Il10(-/-) mice) and Ints(ΔCont);Il10(-/-) (control) mice. Colon tissues were collected and histological, transmission electron microscopy, and gene expression analysis were performed. Fecal microbiota samples were analyzed by sequencing of 16S ribosomal RNA genes. We disrupted Tlr4 in Ints(ΔPten/ΔPten);Il10(-/-) mice. Lipopolysaccharide signaling via TLR4 was blocked by treating mice with polymyxin B.
RESULTS: Il10(-/-) mice developed colitis when they were 6 to 7 months old, whereas Ints(ΔPten/ΔPten);Il10(-/-) mice developed severe colitis and colon tumors by the time they were 36 days old. Within 3 months of birth, 80% of Ints(ΔPten/ΔPten);Il10(-/-) mice developed severe colitis and colonic malignancy, whereas none of the Ints(ΔCont);Il10(-/-) mice had these phenotypes. Ints(ΔPten/ΔPten);Il10(-/-) mice had alterations in fecal microbiota compared with controls, such as increased proportions of Bacteroides species, which are gram negative. Disruption of Tlr4 or treating Ints(ΔPten/ΔPten);Il10(-/-) mice with polymyxin B delayed the development of colitis and reduced disease severity.
CONCLUSIONS: Disruption of Pten in the intestinal epithelium of Il10(-/-) mice speeds the onset and increases the severity of colitis. Fecal microbiota from Ints(ΔPten/ΔPten);Il10(-/-) mice have increased proportions of Bacteroides species. Development of colitis is delayed and reduced by blocking TLR4 signaling. Ints(ΔPten/ΔPten);Il10(-/-) mice may be studied as a model for early-onset ulcerative colitis and used to identify new therapeutic targets.

Related: IL10 Signal Transduction

Mezey G, Treszl A, Schally AV, et al.
Prognosis in human glioblastoma based on expression of ligand growth hormone-releasing hormone, pituitary-type growth hormone-releasing hormone receptor, its splicing variant receptors, EGF receptor and PTEN genes.
J Cancer Res Clin Oncol. 2014; 140(10):1641-9 [PubMed] Related Publications
PURPOSE: Glioblastoma (GB) is the most frequent brain tumor. Despite recent improvement in therapeutic strategies, the prognosis of GB remains poor. Growth hormone-releasing hormone (GHRH) may act as a growth factor; antagonists of GHRH have been successfully applied for experimental treatment of different types of tumors. The expression profile of GHRH receptor, its main splice variant SV1 and GHRH have not been investigated in human GB tissue samples.
METHODS: We examined the expression of GHRH, full-length pituitary-type GHRH receptor (pGHRHR), its functional splice variant SV1 and non-functional SV2 by RT-PCR in 23 human GB specimens. Epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog gene (PTEN) expression levels were also evaluated by quantitative RT-PCR. Correlations between clinico-pathological parameters and gene expressions were analyzed.
RESULTS: Expression of GHRH was found to be positive in 61.9 % of samples. pGHRH receptor was not expressed in our sample set, while SV1 could be detected in 17.4 % and SV2 in 8.6 % of the GB tissues. In 65.2 and 78.3 % of samples, significant EGFR over-expression or PTEN under-representation could be detected, respectively. In 47.8 % of cases, EGFR up-regulation and PTEN down-regulation occurred together. Survival was significantly poorer in tumors lacking GHRH expression. This worse prognosis in GHRH negative group remained significant even if SV1 was also expressed.
CONCLUSION: Our study shows that GHRH and SV1 genes expressed in human GB samples and their expression patterns are associated with poorer prognosis.

Related: EGFR

Lang Y, Xu S, Ma J, et al.
MicroRNA-429 induces tumorigenesis of human non-small cell lung cancer cells and targets multiple tumor suppressor genes.
Biochem Biophys Res Commun. 2014; 450(1):154-9 [PubMed] Related Publications
Lung cancer is the major cause of cancer death globally. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression. Aberrant expression of microRNA (miRNA) has been implicated in cancer initiation and progression. In this study, we demonstrated that the expression of miR-429 are often upregulated in non-small cell lung cancer (NSCLC) compared with normal lung tissues, and its expression level is also increased in NSCLC cell lines compared with normal lung cells. Overexpression of miR-429 in A549 NSCLC cells significantly promoted cell proliferation, migration and invasion, whereas inhibition of miR-429 inhibits these effects. Furthermore, we demonstrated that miR-429 down-regulates PTEN, RASSF8 and TIMP2 expression by directly targeting the 3'-untranslated region of these target genes. Taken together, our results suggest that miR-429 plays an important role in promoting the proliferation and metastasis of NSCLC cells and is a potential target for NSCLC therapy.

Related: Apoptosis Non-Small Cell Lung Cancer Lung Cancer

Nagy E, Gajjar KB, Patel II, et al.
MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases.
Br J Cancer. 2014; 110(12):2874-80 [PubMed] Article available free on PMC after 10/06/2015 Related Publications
BACKGROUND: Tamoxifen has anti-oestrogenic and anti-tumour activity in the breast, but is oestrogenic and carcinogenic in the endometrium. It can induce experimental tumours by both hormonal and DNA-damaging mechanisms, but its carcinogenic mode of action in human endometrium remains unclear.
METHODS: We investigated whether an epigenetic mechanism, involving promoter hypermethylation of the gene for the DNA repair enzyme MGMT (O6-methylguanine DNA methyltransferase), was associated with K-RAS, TP53 and PTEN mutations in endometrial tumours from women treated with tamoxifen (TAM, n=30) or unexposed to the drug (EC, n=38).
RESULTS: There were significant (P<0.05) differences in tumour grade between the TAM and EC groups, with more favourable morphology in the latter. K-RAS mutations, predominantly G>A, occurred in small numbers in both groups. TP53 mutations were of mainly A>G, C>T and indel modifications in both groups, but more frequent in TAM cases. PTEN mutations dominated in EC tumours and were of the type that has large impact on protein function, such as indel or nonsense mutations. These observations alongside the mutational spectrum in PTEN suggest that the malignancies arise from different backgrounds, hence pointing to an effect of tamoxifen. Both groups displayed MGMT promoter hypermethylation. This coincided with mutations more frequently in the TAM (78%) than in the EC (50%) group, even though there were significantly (P<0.05) fewer mutations and methylations in TAM cases.
CONCLUSIONS: Although the difference in coincidence did not reach significance with the current sample size, the findings suggest that epigenetic processes may play a role in the way tamoxifen induces endometrial cancer.

Related: Endometrial (Uterus) Cancer Endometrial Cancer TP53

Yang TS, Yang XH, Chen X, et al.
MicroRNA-106b in cancer-associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTEN.
FEBS Lett. 2014; 588(13):2162-9 [PubMed] Related Publications
It is well established that the interaction between cancer cells and microenvironment has a critical role in tumor development, but the roles of miRNAs in this interaction are rarely known. Here, we have shown that miR-106b is up-regulated in cancer associated fibroblasts compared with normal fibroblasts established from patients with gastric cancer, the expression level of miR-106b is associated with poor prognosis of patients, and CAFs with down-regulated miR-106b could significantly inhibit gastric cancer cell migration and invasion by targeting PTEN. Taken together, these data suggest that miR-106b might be a novel candidate target for the treatment of gastric cancer.

Related: Stomach Cancer Gastric Cancer

Montales MT, Melnyk SB, Simmen FA, Simmen RC
Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.
Carcinogenesis. 2014; 35(9):2102-12 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.

Oshrine BR, Olsen MN, Heneghan M, et al.
Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor.
Cancer Genet. 2014; 207(4):153-9 [PubMed] Related Publications
Previous reports have described an association between hematologic malignancies (HMs) and extragonadal germ cell tumor (GCT). Most patients have been adolescent males with mediastinal nonseminomatous GCT. Although a variety of HMs have been reported, there is a striking predilection toward acute megakaryoblastic leukemia (AMKL). Shared cytogenetic anomalies--particularly isochromosome 12p [i(12p)]--have suggested common clonal origins to the tumors. We report the case of a 17-year-old boy presenting with AMKL and a synchronous mediastinal GCT, with the characteristic i(12p) in both neoplasms. The common clonal origin of the AMKL and GCT was further confirmed with massively parallel sequencing, which identified somatic TP53 and PTEN mutations, as well as a rare germline ATM variant. Although these represent commonly mutated genes in cancer, this combination of mutations is not typically associated with either GCT or AMKL, suggesting that these tumors may represent unique biologic entities when they co-occur.

Related: Chromosome 12 FISH Germ Cell Tumors TP53

Brugarolas J
Molecular genetics of clear-cell renal cell carcinoma.
J Clin Oncol. 2014; 32(18):1968-76 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.

Related: Kidney Cancer VHL BAP1 gene

Miething C, Scuoppo C, Bosbach B, et al.
PTEN action in leukaemia dictated by the tissue microenvironment.
Nature. 2014; 510(7505):402-6 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.

Related: Leukemia Signal Transduction

Xu C, Fillmore CM, Koyama S, et al.
Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression.
Cancer Cell. 2014; 25(5):590-604 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

Related: Lung Cancer


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Cite this page: Cotterill SJ. PTEN, Cancer Genetics Web: http://www.cancerindex.org/geneweb/PTEN.htm Accessed: date

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