PTEN
is a tumor suppressor gene that classically dampens the PI3K AKT mTOR growth-promoting signaling cascade.
PTEN
dysfunction causes dysregulation of this and other pathways, resulting in ...overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline
PTEN
mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline
PTEN
mutations. With time, it became evident that
PTEN
mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of
PTEN
hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms.
The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), ...featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.
Pheochromocytoma and Paraganglioma Neumann, Hartmut P H; Young, Jr, William F; Eng, Charis
The New England journal of medicine,
08/2019, Letnik:
381, Številka:
6
Journal Article
An average of 10% of all cancers (range 1-40%) are caused by heritable mutations and over the years have become powerful models for precision medicine practice. Furthermore, such cancer ...predisposition genes for seemingly rare syndromes have turned out to help explain mechanisms of sporadic carcinogenesis and often inform normal development. The tumor suppressor
encodes a ubiquitously expressed phosphatase that counteracts the PI3K/AKT/mTOR cascade - one of the most critical growth-promoting signaling pathways. Clinically, individuals with germline
mutations have diverse phenotypes and fall under the umbrella term
hamartoma tumor syndrome (PHTS). PHTS encompasses four clinically distinct allelic overgrowth syndromes, namely Cowden, Bannayan-Riley-Ruvalcaba, Proteus and Proteus-like syndromes. Relatedly, mutations in other genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN also predispose patients to partially overlapping clinical manifestations, with similar effects as PTEN malfunction. We refer to these syndromes as '
-opathies.' As a tumor suppressor and key regulator of normal development,
dysfunction can cause a spectrum of phenotypes including benign overgrowths, malignancies, metabolic and neurodevelopmental disorders. Relevant to clinical practice, the identification of
mutations in patients not only establishes a PHTS molecular diagnosis, but also informs on more accurate cancer risk assessment and medical management of those patients and affected family members. Importantly, timely diagnosis is key, as early recognition allows for preventative measures such as high-risk screening and surveillance even prior to cancer onset. This review highlights the translational impact that the discovery of
has had on the diagnosis, management and treatment of PHTS.
Compared to adult carcinomas, there is a paucity of targeted treatments for solid tumors in children, adolescents, and young adults (C-AYA). The impact of germline genomic signatures has implications ...for heritability, but its impact on targeted therapies has not been fully appreciated. Performing variant-prioritization analysis on germline DNA of 1,507 C-AYA patients with solid tumors, we show 12% of these patients carrying germline pathogenic and/or likely pathogenic variants (P/LP) in known cancer-predisposing genes (KCPG). An additional 61% have germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, SMAD7, which we refer to as candidate genes. Despite germline variants in a broad gene spectrum, pathway analysis leads to top networks centering around p53. Our drug-target analysis shows 1/3 of patients with germline P/LP variants have at least one druggable alteration, while more than half of them are from our candidate gene group, which would otherwise go unidentified in routine clinical care.
PTEN
Hamartoma Tumor syndrome (PHTS) encompasses a clinical spectrum of heritable disorders including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, and Proteus and Proteus-like syndrome ...that are associated with germline mutations in the
PTEN
tumor suppressor gene. Breast cancer risk estimates (67–85 %) for women with germline
PTEN
mutations are similar to those quoted for patients with germline mutations in the
BRCA1/2
genes. With
PTEN
on several germline gene testing panels, finding
PTEN
mutations and variants have increased exponentially. PHTS can be differentiated from other hereditary cancer syndromes including Hereditary Breast Ovarian Cancer syndrome, Lynch syndrome, and hamartomatous polyposis syndromes based on personal as well as family history. However, many of the benign features of CS are common in the general population, making the diagnosis of CS challenging. Breast cancer patients with an identified germline
PTEN
mutation are at increased risk of endometrial, thyroid, renal, and colorectal cancers as well as a second breast cancer. Increased screening for the various component cancers as well as predictive testing in first-degree relatives is recommended. Prophylactic mastectomy may be considered especially if breast tissue is dense or if repeated breast biopsies have been necessary. Management of women with breast cancer suspected of CS who test negative for germline
PTEN
mutations should be managed as per a mutation carrier if she meets CS diagnostic criteria, and should be offered enrollment in research to identify other predisposition genes.
Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. ...Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown.
In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19.
This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.
Patients with
hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (
). Such mutations have been associated with a hereditary ...predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for
mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type
who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for
germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative
variants.
The existence of germline
variants was first established in a family with wild-type
who had oligopolyposis and early-onset colon cancers. A validation series indicated that
germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline
variants, particularly the
K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including
related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized
variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without
germline mutations, we confirmed the function of
as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
Without foreknowledge of the complete drug target information, development of promising and affordable approaches for effective treatment of human diseases is challenging. Here, we develop deepDTnet, ...a deep learning methodology for new target identification and drug repurposing in a heterogeneous drug-gene-disease network embedding 15 types of chemical, genomic, phenotypic, and cellular network profiles. Trained on 732 U.S. Food and Drug Administration-approved small molecule drugs, deepDTnet shows high accuracy (the area under the receiver operating characteristic curve = 0.963) in identifying novel molecular targets for known drugs, outperforming previously published state-of-the-art methodologies. We then experimentally validate that deepDTnet-predicted topotecan (an approved topoisomerase inhibitor) is a new, direct inhibitor (IC
50
= 0.43 μM) of human retinoic-acid-receptor-related orphan receptor-gamma t (ROR-γt). Furthermore, by specifically targeting ROR-γt, topotecan reveals a potential therapeutic effect in a mouse model of multiple sclerosis. In summary, deepDTnet offers a powerful network-based deep learning methodology for target identification to accelerate drug repurposing and minimize the translational gap in drug development.
Target identification and drug repurposing could benefit from network-based, rational deep learning prediction, and explore the relationship between drugs and targets in the heterogeneous drug-gene-disease network.
Germline mutations in PTEN account for ~10% of cases of autism spectrum disorder (ASD) with coincident macrocephaly. To explore the importance of nuclear PTEN in the development of ASD and ...macrocephaly, we previously generated a mouse model with predominantly cytoplasmic localization of Pten (Pten
).Cytoplasmic predominant Pten localization results in a phenotype of extreme macrocephaly and autistic-like traits. Transcriptomic analysis of the Pten
cortex found upregulated gene pathways related to myeloid cell activation, myeloid cell migration, and phagocytosis. These transcriptomic findings were used to direct in vitro assays on Pten wild-type and Pten
microglia. We found increased Iba1 and C1q expression with enhanced phagocytic capacity in Pten
microglia, indicating microglial activation. Moreover, through a series of neuron-microglia co-culture experiments, we found Pten
microglia are more efficient at synaptic pruning compared with wild-type controls. In addition, we found evidence for neuron-microglia cross-talk, where Pten
neurons elicit enhanced pruning from innately activated microglia. Subsequent in vivo studies validated our in vitro findings. We observed a concurrent decline in the expression of Pten and synaptic markers in the Pten
cortex. At ~3 weeks of age, with a 50% drop in Pten expression compared with wild-type levels, we observed enhanced activation of microglia in the Pten
brain. Collectively, our data provide evidence that dysregulated Pten in microglia has an etiological role in microglial activation, phagocytosis, and synaptic pruning, creating avenues for future studies on the importance of PTEN in maintaining microglia homeostasis.
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