Somatic activating mutations in <i>PIK3CA</i> cause generalized lymphatic anomaly

Rodríguez‐Laguna, Lara; Agra, Noelia; Ibáñez, Kristina; Oliva-Molina, Gloria; Gordo, Gema; Khurana, Noor; Hominick, Devon; Beato, María; Colmenero, Isabel; Herranz, Gonzalo; Canizalez, Juan M. Torres; Pena, Rebeca Rodríguez; Vallespín, Elena; Martín‐Arenas, Rubén; Pozo, Ángela del; Villaverde, Cristina; Bustamante, Ana; Ayuso, Carmen; Lapunzina, Pablo; López-Gutiérrez, Juan Carlos; Dellinger, Michael T.; Martinez-Glez, Víctor

doi:10.1084/jem.20181353

Cited by 108 publications

(141 citation statements)

References 39 publications

(52 reference statements)

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“…In KLA, these differences might result from the ratio of spindle cells. In recent research, NRAS and PIK3CA mutations were detected in the affected lesions of KLA and GLA patients . Gain‐of‐function mutations in NRAS and PIK3CA could be associated with the pathogenesis of LAs.…”

Section: Discussioncontrasting

confidence: 99%

Potential biomarkers of kaposiform lymphangiomatosis

Ozeki

Nozawa

Kawamoto

et al. 2019

Pediatric Blood & Cancer

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Background Kaposiform lymphangiomatosis (KLA) has recently been distinguished as a novel subtype of generalized lymphatic anomaly (GLA), and is characterized by foci of spindle endothelial cells amid a background of malformed lymphatic channels. The etiology of these diseases remains unknown and diagnosis is confounded by their similar clinical findings. This study aimed to clarify differences in the clinical findings and plasma cytokine profiles of GLA and KLA patients. Procedure Clinical features data of GLA and KLA patients were obtained from a national survey. Differences in clinical findings, plasma levels of cytokines, and survival were analyzed. Plasma was obtained from healthy controls and GLA and KLA patients. Thirty‐six angiogenic and lymphangiogenic factors were evaluated for cytokine concentration. Results Twenty‐one patients with GLA and 11 with KLA were recruited. Mediastinal masses, hemorrhagic pericardial and pleural effusion, coagulation disorders, and thrombocytopenia were more frequent in KLA than in GLA. KLA had a significantly poorer outcome than GLA (P = 0.044). Soluble VEGFR3, angiopoietin 2, HGF, soluble HER2, tenascin C, and soluble HGFR levels were higher in KLA. Notably, soluble VEGFR3 and angiopoietin 2 levels were approximately 10‐fold higher than those of other molecules measured. However, soluble VEGFR1 and soluble TIE2 were lower in KLA than in GLA and the controls. Conclusions Patients with KLA have an unfavorable prognosis and serious symptoms (hemorrhagic pleural effusion and coagulation disorders). Our data indicate that eight angiogenic cytokines might be potential biomarkers of KLA.

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Section: Discussioncontrasting

confidence: 99%

Potential biomarkers of kaposiform lymphangiomatosis

Ozeki

Nozawa

Kawamoto

et al. 2019

Pediatric Blood & Cancer

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“…Somatic mosaic mutations in the PI3K pathway have been associated with a range of subtypes of vascular malformations (reviewed in Ref. 123 ), with PIK3CA mutations driving so-called venous malformations [124][125][126] and lymphatic anomaly 127 .…”

Section: Class I Pi3ks In Human Disease Syndromesmentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

371

364

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Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids which directly activate signal transduction pathways. In addition to being frequently genetically-activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder which predisposes to lymphoma. The class II and III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an indirect impact on cell signalling. Here we summarize current knowledge on the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are stimulated. Areas covered include emerging evidence for isoform-specific regulation and function of Akt family members, potential non-cytotoxic actions of PI3K inhibitors in cancer and regulation of mTORC1 by class II and III PI3Ks. A deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes, and ultimately, in human disease. The cDNA cloning of the first catalytic subunit of a PI3K (p110, Ref. 1) in 1992 revealed close sequence similarity to the Saccharomyces cerevisiae Vps34 gene product, which was soon thereafter documented to possess PI3K activity in that it could convert phosphatidylinositol (PI) to its 3phosphorylated PI(3)P derivative 2. Subsequent bioinformatic and molecular biology approaches based on sequence homology of the kinase domain of these enzymes allowed the isolation of multiple PI3K genes from a range of organisms, with the Waterfield group proposing the now generally-accepted classification of the isoforms of PI3K 3-6. The main role of Vps34 in yeast in regulating the transport of proteins to the lysosome-like vacuole 7 indicates that regulation of vesicular traffic is the most ancient function of 3-phosphoinositides, with a role in signalling being a later addition in eukaryotic evolution 8. Genetic and pharmacological approaches have now uncovered the broad functions of the different PI3K isoforms, some of which are targets of the first approved PI3K inhibitors for the treatment of human cancer. The challenges faced in effectively targeting PI3K in disease have illustrated that much remains to be learned about PI3K biology. In this review, we summarize key recent insights into PI3K signalling and cell biology in mammals, for example, newly discovered human syndromes, resulting from constitutive activation of class I PI3Ks leading to tissue overgrowth 9 or immune deregulation 10, 11. Despite having been discovered over two decades ago 12, 13 , the class II PI3Ks remain the most enigmatic PI3K subfamily. Recent studies have started to uncover mechanisms by which these PI3Ks are regulated and how t...

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“…The mTORC1 phosphorylates the known downstream targets of mTOR; the eukaryotic translation initiation factor 4E‐binding protein (4EBP1) and the ribosomal protein S6 kinase 1 (S6K1), which mediate an increase in protein synthesis and cell growth in lymphangiogenesis 6–10 . In addition, the mutation of PIK3CA (upstream signaling of mTOR) promotes mTOR pathway and causes LM 1,11 . Thus, expression of the mTOR signaling pathway might play a key role in pathogenesis of lymphatic anomalies.…”

Section: Introductionmentioning

confidence: 99%

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Hori

Ozeki

Hirose

et al. 2020

Pathology International

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The mammalian target of rapamycin (mTOR) inhibitor sirolimus is an effective treatment for difficult‐to‐treat lymphatic anomalies. However, little is known about the expression of mTOR pathway components in lymphatic anomalies. Here we investigated the expression pattern of mTOR pathway components and their phosphorylated forms (mTOR, p‐mTOR, 4EBP1, p‐4EBP1, S6K1 and p‐S6K1) in normal lymphatic vessels and lymphatic anomalies using immunohistochemistry. We studied 18 patients of lymphatic anomalies, including lymphatic malformation (LM, n = 14), Kaposiform lymphangiomatosis (KLA, n = 2) and Kaposiform hemangioendothelioma (KHE, n = 2). Normal lymphatic vessels expressed 4EBP1, S6K1 and p‐S6K1, but not p‐4EBP1, mTOR or p‐mTOR. The mTOR was detected in all lymphatic anomalies, whereas its activation form p‐mTOR was detected in half cases of KLA and KHE but not in LM. All lymphatic anomalies expressed S6K1 and its activated form p‐S6K1. The expression of 4EBP1 was also found in all lymphatic anomalies, but its activation was detected in approximately half of them. The activation of mTOR was seen in tumor (KLA and KHE) but not in malformation (LM), whereas the activation of S6K1 and 4EBP1 was seen in all and half of lymphatic anomalies, respectively.

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Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

Cited by 108 publications

References 39 publications

Potential biomarkers of kaposiform lymphangiomatosis

Potential biomarkers of kaposiform lymphangiomatosis

PI3K isoforms in cell signalling and vesicle trafficking

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

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