Molecular characterization of epithelioid haemangioendotheliomas identifies novel <i><scp>WWTR</scp>1</i>–<i><scp>CAMTA</scp>1</i> fusion variants

Patel, Nimesh R.; Salim, Alaa A.; Sayeed, Hadi; Sarabia, Stephen F.; Hollingsworth, Faith; Warren, Mikako; Jakacky, Jared; Tanas, Munir R.; Oliveira, André M.; Rubin, Brian P.; Lazar, Alexander J.; López‐Terrada, Dolores; Wang, Wei Lien

doi:10.1111/his.12697

Cited by 74 publications

(52 citation statements)

References 29 publications

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“…Notably, the R331W missense mutation of YAP has recently been linked to a germline risk in lung adenocarcinoma (Chen et al 2015a). Moreover, almost all epithelioid hemangioendotheliomas contain gene fusions of TAZ-CAMTA1, TAZ-FOSB, or YAP-TFE3 (Tanas et al 2011;Antonescu et al 2013;Patel et al 2015), strongly supporting a role of YAP/TAZ in human tumorigenesis.…”

Section: The Yap/taz Transcriptional Programs and Their Functional Oumentioning

confidence: 97%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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Section: The Yap/taz Transcriptional Programs and Their Functional Oumentioning

confidence: 97%

Mechanisms of Hippo pathway regulation

2016

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“…In general, several aspects of GD pathophysiology promote oncogenesis, such as increased glycosphingolipids, alternatively activated macrophages, and modifier genes [5]. Epithelioid hemangioendothelioma has a well-defined genetic association, for example, with translocation and fusion of CAMTA1 and WWTR1 genes on chromosomes 1 and 3 [t(1; 3) (1p36.23; 3q25.1)] [17,18]. Both CAMTA1 and WWTR1 genes have been elucidated to be involved in oncogenesis in multiple studies [19,20].…”

Section: Discussionmentioning

confidence: 99%

Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population

et al. 2016

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An Ashkenazi Jewish male first presented at age 40 with persistent bone pain and a tender mass on his right leg. This patient was the subject of a prior case report in 1995 [1]. He had onset of persistent bone pain and splenomegaly at age 5 years and at age 10 suffered from avascular osteonecrosis of the right femur. At age 15 years, he suffered from recurrent avascular necrosis of right femur and right humerus. Diagnosis of Gaucher Disease (GD) Type 1 was made on bone marrow biopsy, later confirmed by low leucocyte acid b-glucosidase activity and the finding of homozygosity for N370S mutation in GBA gene. He underwent osteotomy of his right hip at age 18. At age 25 years, the patient suffered from infectious mononucleosis resulting in massive splenomegaly and splenic rupture that necessitated emergency splenectomy. Subsequently, he underwent right hip replacement. At his presentation with right leg mass, the mass and bone pain had been present for the previous 6 months and had worsened until the patient could no longer continue his daily activities. At this time in 1992, enzyme replacement therapy had not yet become the standard of care for GD.Gaucher disease, an autosomal recessive disorder, is a prototype inborn error of metabolism due to biallelic mutations in GBA1 that results in deficiency of lysosomal acid b-glucocerebrosidase, a key enzyme in the degradation pathway of membrane glycosphingolipids [2]. GD displays a heterogeneous clinical presentation affecting multiple organs with major skeletal involvement based on the accumulation of glucocerebroside-laden macrophages, eponymously known as Gaucher cells [3]. The accumulation of primary substrate leads to generation of bioactive lipids that cause immune activation and chronic metabolic inflammation [4,5]. Bone disease was more common and more severe in asplenic patients with GD [2]. In fact, asplenia is a major independent risk factor for avascular osteonecrosis [6].Plain radiographs of tibia showed typical bony lesions of Gaucher disease including osteopenia, extensive bone marrow infarcts, and lytic lesions. In addition, there was a focal mass concerning for a malignant tumor. The tibia was resected and replaced with intercalary allograft, soleus muscle flap, and split thickness skin graft. Subsequently, infectious complications necessitated an above knee amputation.On gross examination, the tumor measured 4 3 4 3 3 cm and was focally friable and hemorrhagic. The tumor was dispersed in sheets and cords within a hyalinized basophilic background. Intensely eosinophilic nucleoli, abundant cytoplasm, and cytoplasmic vacuoles with red blood cells were present. The extraosseous segment showed increasing atypia with primitive anastomosing split like vascular spaces. The bone marrow was extensively necrotic and demonstrated infiltration by Gaucher cells. By immunohistochemistry, the cells stained positive for keratin, factor VIII antigen, Ulex europaeus agglutinin, and vimentin [1]. The cells demonstrated a high nuclear cytoplasmic ratio with striking euchrom...

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“…EHE carries a disease-defining genetic mutation of t (1;3)(p36.3;q25) involving a fusion transcript where exon 4 of WWTR1 is fused in frame with either exon 8 or exon 9 of CAMTA1 [4]. An alternative fusion transcript of YAP1-TFE3 or novel WWTR1-CAMTA1 fusion variants have also been observed and may bear significance on clinical behavior and variant morphology [5,6]. CAMTA1 is a transcription factor and putative tumor suppressor [7].…”

Section: Discussionmentioning

confidence: 99%

Hepatic Epithelioid Hemangioendothelioma with Cecal Metastasis in a Natural Course: A Case Report

Chen¹,

Lai²

2016

J Cytol Histol

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Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of low malignant potential that occurs mostly in soft tissue. So far, only two cases of EHE involving the intestine have been recorded. Here, we describe a rare case of cecal EHE due to a subsequent metastasis from the primary liver tumor three years after initial diagnosis. A 74-year-old man had sudden onset of epigastralgia for 24 hours. The abdominal CT revealed an ileocecal mass with a small bowel obstruction, and extensive tumor involvement in the liver was noted. He received an emergent right hemicolectomy for relief of the ileus. Unfortunately, he expired four days later due to septic shock. The pathologic diagnosis of EHE prompted a molecular study for a WWTR1-CAMTA1 fusion. The Sanger sequencing results showed the fusion involved exon 4 of WWTR1 with exon 8 of CAMTA1. There is no standard treatment for hepatic EHE because of its rarity and variable clinical outcome. The decision on a treatment strategy should be individualized for each patient. Since the patient received supportive care only for the liver tumor, this case demonstrated a natural course of hepatic EHE with a survival of more than 3.3 years.

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Molecular characterization of epithelioid haemangioendotheliomas identifies novel WWTR1–CAMTA1 fusion variants

Abstract: This study confirms the high incidence of WWTR1-CAMTA1 and YAP1-TFE3 rearrangements in EHE and indicates that the staining pattern for TFE3 IHC is critical for specificity.

Cited by 74 publications

References 29 publications

Mechanisms of Hippo pathway regulation

Mechanisms of Hippo pathway regulation

Case series and literature review of skeletal tumors and their incidence in the Gaucher disease population

Hepatic Epithelioid Hemangioendothelioma with Cecal Metastasis in a Natural Course: A Case Report

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