Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome.
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Researchers begin to map the epigenetic methylation of excessive brain connections in Autism.

Researchers begin to map the epigenetic methylation of excessive brain connections in Autism. | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
Recent research has linked autism with a lack of pruning in developing brain connections, but a new Dartmouth study suggests instead it is the excessive growth of new connections that causes sensory overload in people with the disorder.  The results, which have broad implications for understanding the neurobiological basis of autism spectrum disorders, appear inThe…
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PTEN Hamartoma Tumor Syndrome (PHTS) - GeneReviews® - NCBI Bookshelf

PTEN Hamartoma Tumor Syndrome (PHTS) - GeneReviews® - NCBI Bookshelf | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

Updated 2016:

 

'PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome.



A presumptive diagnosis of PHTS is based on clinical signs; by definition, however, the diagnosis of PHTS is made only when a PTEN pathogenic variant is identified.


 The prevalence has been estimated at one in 200,000 [Nelen et al 1999], likely an underestimate. 


Bennett et al [2010] determined that approximately 30% of individuals with Cowden syndrome (CS) (OMIM) and Cowden-like syndrome who do not have a PTEN germline pathogenic variant have a germline KLLN methylation epimutation ... Pilot data suggest that individuals with CS and Cowden-like syndrome with a germline KLLN epimutation have a greater prevalence of breast and renal cell carcinomas than do those with a germline PTEN pathogenic variant. 

 A pilot study found that individuals with Cowden syndrome (CS) and a CS-like (CSL) disorder without germline PTEN pathogenic variants (but with increased levels of manganese superoxide dismutase) harbored germline variants in SDHB (OMIM) and SDHD (OMIM) [Ni et al 2008].

... germline variants in SDHB, SDHC, and SDHD occur in approximately 10% of persons with CS or CSL who do not have a PTEN pathogenic variant has been validated in an independent series of 608 research participants [Ni et al 2012]. 

Approximately 10% of individuals with CS/CSL disorder without germline PTEN or SDHx pathogenic variants have been found to harbor germline PIK3CA (see PIK3CA-Related Segmental Overgrowth) or AKT1 pathogenic variants [Orloff et al 2013]. 

Another 3%-6% of CS and CS-like individuals without pathogenic variants in the above known genes have germline heterozygous SEC23B pathogenic variants, which are particularly associated with thyroid carcinoma [Yehia et al 2015].


Tumor risks:

 

Individuals with CS are at high risk for breast, thyroid, and endometrial cancers. As with other hereditary cancer syndromes, the risk of multifocal and bilateral (in paired organs such as the breasts) cancer is increased:

 

Breast disease:

 

Women with Cowden syndrome are at as high as a 67% risk for benign breast disease.

 

A recent analysis of prospectively accrued and followed probands and family members with a PTEN pathogenic variant reveal an 85% lifetime risk for female breast cancer, with 50% penetrance by age 50 years [Tan et al 2012].

 

Although breast cancer has been described in males with a PTEN pathogenic variant [Fackenthal et al 2001], it was not observed in a recent study of more than 3000 probands [Tan et al 2011].

 

Thyroid disease:

 

Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [Harach et al 1999].

 

The lifetime risk for epithelial thyroid cancer is approximately 35% [Tan et al 2012]. Median age of onset was 37 years; seven years was the youngest age at diagnosis [Ngeow et al 2011]. 

 

Endometrial disease:

 

Benign uterine fibroids are common.

 

Lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [Tan et al 2012].

 

 

Gastrointestinal neoplasias:

 

More than 90% of individuals with a PTEN pathogenic variant who underwent at least one upper or lower endoscopy were found to have polyps [Heald et al 2010].

 

Histologic findings varied, ranging from ganglioneuromatous polyps, hamartomatous polyps, and juvenile polyps to adenomatous polyps.

 

Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [Tan et al 2012].

 

 

Renal cell carcinoma:

 

Lifetime risk for renal cell carcinoma is estimated at 35%, with the starting age at risk in the 40s [Tan et al 2012].

 

The predominant histology is papillary renal cell carcinoma [Mester et al 2012].

 

 

Other Lifetime risks:

 

...cutaneous melanoma is estimated at more than 5%.

 

Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS. Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS.

 

A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease) is also found in CS and may be pathognomonic.

 

 

Autism/pervasive developmental disorder and macrocephaly:

 

Approximately 20% of individuals with autism spectrum disorders and macrocephaly have germline PTEN pathogenic variants. 


The 10%-20% prevalence of germline PTEN pathogenic variants in autism spectrum disorders with macrocephaly has now been confirmed by several independent groups [Herman et al 2007a, Herman et al 2007b, Orrico et al 2009, Varga et al 2009].'

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Involvement of IGF-2, IGF-1R, IGF-2R and PTEN in development of human tooth germ - an immunohistochemical study. - PubMed - NCBI

Organogenesis. 2016 Jul 2;12(3):152-167. Epub 2016 Jun 21. Research Support, Non-U.S. Gov't
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PI3K Isoforms Have Spatially Distinct Roles in PTEN Hamartoma Tumor Syndrome

PI3K Isoforms Have Spatially Distinct Roles in PTEN Hamartoma Tumor Syndrome | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

2013:


'A clinically relevant dose of BKM120 also induced rapid, dramatic regression of advanced hamartomas. 


In addition to revealing spatially distinct roles of PI3K isoforms in the skin, these findings provide a rationale for use of PI3K inhibitors to prevent and treat hamartomas in patients with PHTS.'

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How PTEN May Play A Role In Vascular Disease Pathogenesis

How PTEN May Play A Role In Vascular Disease Pathogenesis | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it


2018:


'Altered hemodynamic forces can result in SMC [smooth muscle cell]  PTEN deficiency, which appears to be associated with SMC dedifferentiation and vascular fibrosis.'

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Experimental drug suppresses new defective PTEN cancer pathway, study finds

Experimental drug suppresses new defective PTEN cancer pathway, study finds | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

2017:


'The investigation found that the drug, geranylgeranyltransferase inhibitor GGTI-2418 suppresses a new defective PTEN cancer pathway discovered by Pagano's group.'

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Uncommon hereditary gynaecological tumour syndromes: pathological features in tumours that may predict risk for a germline mutation. - PubMed - NCBI

Uncommon hereditary gynaecological tumour syndromes: pathological features in tumours that may predict risk for a germline mutation. - PubMed - NCBI | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

'Early diagnosis of an inherited syndrome permits early screening, detection, and management of additional malignancies associated with the syndrome. 


This review highlights these rare syndromes and their tumour pathology, including Peutz-Jeghers syndrome (gastric type mucinous carcinoma of the cervix; ovarian sex cord tumour with annular tubules); hereditary leiomyoma renal cell carcinoma syndrome (uterine leiomyoma); tuberous sclerosis complex (uterine PEComa; uterine lymphangioleiomyomatosis); DICER1 syndrome (ovarian Sertoli-Leydig cell tumour; cervical embryonal rhabdomyosarcoma); rhabdoid tumour predisposition syndrome 2 (small cell carcinoma of the ovary, hypercalcaemic type); Cowden syndrome (endometrial endometrioid adenocarcinoma); naevoid basal cell carcinoma syndrome (ovarian fibroma); and Von Hippel-Lindau syndrome (clear cell papillary cystadenoma of the broad ligament).'

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An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region

An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
Several autosomal dominant inherited tumour syndromes demonstrate prominent features in the oral and maxillofacial region. Although multiple organ systems are frequently involved, the target organs more frequently affected are the skin (nevoid basal cel
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PTEN in smooth muscle cells is essential for colonic immune homeostasis. - Abstract - Europe PMC

'Colonic immune homeostasis is essential for normal gastrointestinal tract functioning. 


In this study, we report that specific gene targeting of phosphatase and tensin homolog (PTEN) in smooth muscle cells caused age-related colonic lymphoid hyperplasia followed by global immune activation in mice.' 

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The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein

The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

'Despite its risky profile as a tumor suppressor, PTEN continues to attract substantialinterest as a therapeutic target. 


We present current strategies toward PTEN modulation,
and we discuss how recent advances could accelerate the design of future PTEN modulators considering the protein, its mRNA, and related miRNAs as targets.'

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Severe Radiation Toxicity Associated with a Germline PTEN Mutation

'To our knowledge, this is the first reported case of unexpected normal tissue toxicity following radiotherapy in the setting of a germline PTEN mutation. 

This observation is consistent with prior experimental studies in cell culture, which have predicted an association between germline PTEN loss-of-function mutations and hypersensitivity of normal tissues to radiotherapy. 

Caution with radiotherapy is recommended until this observation can be studied further in larger cohorts of Cowden syn- drome patients.'
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Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS)

Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS) | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases o
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Dartmouth Study Provides New Insights into Genetic Mutations in Autism –

Dartmouth Study Provides New Insights into Genetic Mutations in Autism – | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

“This discovery gives us new insight into how PTEN works to regulate neuronal growth, and suggests that a strategy regulating the location of PTEN within cells could be therapeutic for autism spectrum disorders.”

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comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes | Human Molecular Genetics | Oxford Academic

comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes | Human Molecular Genetics | Oxford Academic | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

'Our findings reveal distinctive functional patterns among PTEN mutations found in tumors and in the germline of PHTS and ASD patients, which could be relevant for therapy.'

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ScienceDirect

MULTIPLE HAMARTOMA SYNDROME

'Not all patients with CS clinically have PTEN mutations.

Approximately 30% of such patients have a germline KLLN epimutation, which is associated with a greater frequency of breast and renal carcinoma. 

Germline variants in three of the succinate dehyrogenase genes (B, C and D) have also been reported in both PTEN-positive and PTEN-negative CS patients; in the former they appear to modify the risk of breast and thyroid cancer.'
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Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells. - PubMed - NCBI

Simvastatin induces apoptosis in PTEN‑haploinsufficient lipoma cells. - PubMed - NCBI | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

2018:


'Adipose tissue tumors (lipomas) frequently develop in patients with heterozygous germ line phosphatase and tensin homolog (PTEN) mutations. 


Simvastatin has been demonstrated to exhibit antitumor effects, and so the aim of the present study was to assess the effects of simvastatin on the growth of human PTEN haploinsufficient lipoma cells.


The results of the present study suggest that simvastatin may be beneficial for patients with inoperable PTEN haploinsufficient lipomas.'

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Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer | Breast Cancer Research | Full Text

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer | Breast Cancer Research | Full Text | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. 


While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers.  


Six genes showed PTEN-SSL patterns of activity in a large proportion of PTEN-deficient breast cancer cell lines and are potential specific vulnerabilities in PTEN-deficient breast cancer. 


Furthermore, the NUAK1 PTEN-SSL vulnerability identified by RNA interference techniques can be recapitulated and exploited using the small molecule kinase inhibitor HTH-01-015. 


Thus, NUAK1 inhibition may be an effective strategy for precision treatment of PTEN-deficient breast tumors.'

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The Roles of P53, BRCA1, and PTEN in Hereditary Cancers – Lauren Fitzgerald, Contributor | Cancer Biology

The Roles of P53, BRCA1, and PTEN in Hereditary Cancers – Lauren Fitzgerald, Contributor | Cancer Biology | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
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With Regard to PTEN Promoter Testing for Hereditary Cancer Risk Assessment | JCO Precision Oncology

With Regard to PTEN Promoter Testing for Hereditary Cancer Risk Assessment | JCO Precision Oncology | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
'Our laboratory, however, does not currently classify any PTEN promoter variant as pathogenic or likely pathogenic. 

Thus, we also question the clinical utility of including this region in clinical diagnostic testing and offer our laboratory’s experience in support of the proposal that analysis of the full PTEN promoter region may not be beneficial as a component of hereditary cancer panel testing.'
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Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway

Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

Mosaicism is the presence of two or more genetically distinct cell lineages originating from a single zygote. 


The skin frequently marks mosaic conditions through migration patterns of a population of mutant cells during embryogenesis. 


Somatic mutations in any of the genes in the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway may result in a spectrum of abnormal growth ranging from an isolated small skin lesion with minimal or no overgrowth to extensive skin involvement with striking extremity enlargement and tumor susceptibility.'

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Association of genetic polymorphisms in PTEN and additional interaction with alcohol consumption and smoking on colorectal cancer in Chinese population

Association of genetic polymorphisms in PTEN and additional interaction with alcohol consumption and smoking on colorectal cancer in Chinese population | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
Aims: To investigate the association of phosphatase and tensin homologue deleted on chromosome ten (PTEN) gene rs3830675, and additional interaction with drinking and smoking on colorectal cancer (CRC), based on a hospital based Chinese case-control study
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Rare diseases in general practice: recognising the zebras among the horses

Rare diseases in general practice: recognising the zebras among the horses | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
'Patients frequently describe a long and protracted ‘diagnostic odyssey’, taking years, or even decades. 

These years can be defined by uncertainty, multiple hospital attendances, investigations, misdiagnoses, and inappropriate treatments; with huge emotional cost and wasted time, effort and resources.  

Even in the absence of a disease-specific therapy, a prompt and accurate diagnosis is of huge value. Early diagnosis can put an end to the exhausting diagnostic odyssey and diagnosis validates the individual’s symptomatology. 

It can help inform family planning, especially for inherited paediatric diseases where several children in a family may be affected before diagnosis, it informs prognosis and importantly, it assists the patient and family in gaining access to social and educational support.'
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Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review | Radioprotection

Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review | Radioprotection | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
'We conclude that the risk of radio-induced BC in BRCA mutation carriers depends on age at exposure and that repeated X-ray breast exposures such as mammography should be used very cautiously in these mutated patients.'
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Do Your Genes Increase Your Risk of Getting Cancer Twice? –

Do Your Genes Increase Your Risk of Getting Cancer Twice? – | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
'Likewise, we found that men with the PTEN mutation have a much higher risk for a second primary thyroid cancer. 

That has implications for surgery. 

Often a surgeon treating thyroid cancer will leave part of the thyroid intact. 

But for men with such a high risk, the surgeon may want to remove all of the thyroid. 

Doing so would decrease the man’s chances of developing a second cancer.'
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PTEN hamartoma syndrome: unravelling the complexities of childhood screening

PTEN hamartoma syndrome: unravelling the complexities of childhood screening | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
'Available guidance for the management in childhood of PHTS patients is limited. 

The lack of paediatric reports of PHTS-associated cancer may be explained by previous diagnostic limitations. 

We recommend yearly physical examination (particularly of skin and thyroid) and yearly thyroid ultrasound upon diagnosis. 

In view of the high lifetime risk of malignancy it is important to keep patients under close surveillance.'
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Red wine compound increases anti-tumor effect of rapamycin

Red wine compound increases anti-tumor effect of rapamycin | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it

'Researchers have discovered that resveratrol -- a compound found in red wine -- when combined with rapamycin can have a tumor-suppressing effect on breast cancer cells that are resistant to rapamycin alone. 


The research also indicates that the PTEN tumor-suppressing gene contributes to resveratrol's anti-tumor effects in this treatment combination.'

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PTEN hamartoma tumour syndrome: early tumour development in children. - PubMed - NCBI

PTEN hamartoma tumour syndrome: early tumour development in children. - PubMed - NCBI | Cowden's Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, PTEN Hamartoma Tumour Syndrome. | Scoop.it
Arch Dis Child. 2015 Jan;100(1):34-7. doi: 10.1136/archdischild-2014-305997. Epub 2014 Aug 11.
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