PTEN-Related Overgrowth Syndromes

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.

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The Skin in Cowden Syndrome

Frontiers in Medicine ◽

10.3389/fmed.2021.658842 ◽

2021 ◽

Vol 8 ◽

Author(s):

Agnes Lim ◽

Joanne Ngeow

Keyword(s):

Targeted Therapies ◽

Autosomal Dominant ◽

Malignant Tumors ◽

Skin Lesions ◽

Cowden Syndrome ◽

Differential Diagnoses ◽

Phosphatase And Tensin Homolog ◽

Autosomal Dominant Condition ◽

Tensin Homolog ◽

Dominant Condition

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.

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A Pediatric Case of Cowden Syndrome with Graves’ Disease

Case Reports in Pediatrics ◽

10.1155/2017/2750523 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

Cláudia Patraquim ◽

Vera Fernandes ◽

Sofia Martins ◽

Ana Antunes ◽

Olinda Marques ◽

...

Keyword(s):

Treatment Options ◽

Antithyroid Drug ◽

Human Tumor ◽

Suppressor Gene ◽

Cowden Syndrome ◽

Graves Disease ◽

Multisystem Disorder ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Coarse Facies

Cowden syndrome (CS) is a rare dominantly inherited multisystem disorder, characterized by an extraordinary malignant potential. In 80% of cases, the human tumor suppressor gene phosphatase and tensin homolog (PTEN) is mutated. We present a case of a 17-year-old boy with genetically confirmed CS and Graves’ disease (GD). At the age of 15, he presented with intention tremor, palpitations, and marked anxiety. On examination, he had macrocephaly, coarse facies, slight prognathism, facial trichilemmomas, abdominal keratoses, leg hemangioma, and a diffusely enlarged thyroid gland. He started antithyroid drug (ATD) therapy with methimazole and, after a 2-year treatment period without achieving a remission status, a total thyroidectomy was performed. Diagnosis and management of CS should be multidisciplinary. Thyroid disease is frequent, but its management has yet to be fully defined. The authors present a case report of a pediatric patient with CS and GD and discuss treatment options.

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Esthetic and Functional Improvement of Asymmetric Lower Limb Overgrowth in a Proteus Syndrome Patient: a Combined Surgical Technique

Indian Journal of Surgery ◽

10.1007/s12262-021-02773-7 ◽

2021 ◽

Author(s):

Francesca Riccardi ◽

Simone Catapano ◽

Giuseppe Cottone ◽

Dino Zilio ◽

Luca Vaienti

Keyword(s):

Adipose Tissue ◽

Lower Limb ◽

Vascular Malformations ◽

Functional Improvement ◽

Proteus Syndrome ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Genetic Mosaicism ◽

Phosphoinositide 3 Kinase ◽

The Right

AbstractProteus syndrome is a rare, sporadic, congenital syndrome that causes asymmetric and disproportionate overgrowth of limbs, connective tissue nevi, epidermal nevi, alteration of adipose tissue, and vascular malformations. Genetic mosaicism, such as activating mutations involving protein kinase AKT1, phosphoinositide 3 kinase (PI3-K), and phosphatase and tensin homolog (PTEN), may be important causes of Proteus syndrome. However, many patients have no evidence of mutations in these genes. Currently, the diagnosis is clinical and based on phenotypic features. This article reports a case of Proteus syndrome in a 14-year-old female patient who presented with linear epidermal nevi, viscera anomalies, and adipose tissue dysregulation. She showed an asymmetric progressive overgrowth of the right lower limb after birth bringing relevant functional and esthetic consequences. Therefore, she asked a plastic surgery consultation and a surgical treatment with a combined technique was planned. With our approach, we were able to reduce leg diameter and improve joint mobility reliably and safely with satisfying esthetic results.

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Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

Cancers ◽

10.3390/cancers12071719 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1719

Author(s):

Timothy J. Lavelle ◽

Tine Norman Alver ◽

Karen-Marie Heintz ◽

Patrik Wernhoff ◽

Vegard Nygaard ◽

...

Keyword(s):

Cell Line ◽

Cell Transformation ◽

Soft Agar ◽

Transformation Process ◽

Loss Of Function ◽

Phosphatase And Tensin Homolog ◽

Akt Activation ◽

Transcriptional Reprogramming ◽

Tensin Homolog ◽

Tyrosine Receptor Kinase

The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.

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The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma

Cancers ◽

10.3390/cancers11081169 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1169 ◽

Cited By ~ 4

Author(s):

Sioletic Stefano ◽

Scambia Giovanni

Keyword(s):

Soft Tissue ◽

Tumor Suppressor ◽

Soft Tissue Sarcoma ◽

Biological Significance ◽

Treatment Strategies ◽

Predictive Biomarkers ◽

Suppressor Gene ◽

Oncogenic Signaling ◽

Tensin Homolog ◽

Pathologic Features

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies.

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Endocrine Manifestations of von Hippel–Lindau Disease

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2013-0520-rs ◽

2015 ◽

Vol 139 (2) ◽

pp. 263-268 ◽

Cited By ~ 27

Author(s):

Clarissa Cassol ◽

Ozgur Mete

Keyword(s):

Neuroendocrine Tumors ◽

Autosomal Dominant ◽

Suppressor Gene ◽

Autosomal Dominant Disorder ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Sporadic Cases ◽

Vhl Disease

von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

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Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

Endocrine Related Cancer ◽

10.1530/erc-15-0203 ◽

2015 ◽

Vol 22 (5) ◽

pp. 687-701 ◽

Cited By ~ 8

Author(s):

Jaesung (Peter) Choi ◽

Reena Desai ◽

Yu Zheng ◽

Mu Yao ◽

Qihan Dong ◽

...

Keyword(s):

Androgen Receptor ◽

Uterine Cancer ◽

Serum Testosterone ◽

Cowden Syndrome ◽

Corpora Lutea ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Uterine Growth ◽

Uterine Cancers ◽

Reproductive Cancers

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

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Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

Journal of Experimental Medicine ◽

10.1084/jem.20110571 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1835-1847 ◽

Cited By ~ 78

Author(s):

Gwénola Boulday ◽

Noemi Rudini ◽

Luigi Maddaluno ◽

Anne Blécon ◽

Minh Arnould ◽

...

Keyword(s):

Autosomal Dominant ◽

Vascular Malformations ◽

Vascular Lesions ◽

Developmental Timing ◽

Cerebral Cavernous Malformations ◽

Loss Of Function ◽

Cavernous Malformations ◽

The Central Nervous System ◽

Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

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Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e21063 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e21063-e21063

Author(s):

Rachael Hagen ◽

Joanna Amy Kolodney ◽

Jessica Patterson ◽

Michael Kolodney

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Somatic Mutation ◽

Autosomal Dominant ◽

Genetic Relationships ◽

Suppressor Gene ◽

Loss Of Function ◽

Whole Exome ◽

The Subject ◽

Autosomal Dominant Inheritance Pattern

e21063 Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G > A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G > A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.

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