Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans

Science Translational Medicine

Volumn 8, Issue 332, 2016, Pages

  Castillo, Sandra D ^a   Tzouanacou, Elena ^b,c   Zaw Thin, May ^d   Berenjeno, Inma M ^a   Parker, Victoria E R ^e   Chivite, Iñigo ^f   Milà Guasch, Maria ^a   Pearce, Wayne ^a   Solomon, Isabelle ^a   Angulo Urarte, Ana ^f   Figueiredo, Ana M ^f   Dewhurst, Robert E ^b,n,o   Knox, Rachel G ^e   Clark, Graeme R ^g   Scudamore, Cheryl L ^h   Badar, Adam ^d   Kalber, Tammy L ^d   Foster, Julie ⁱ   Stuckey, Daniel J ^d   David, Anna L ^d   Phillips, Wayne A ^j,k   Lythgoe, Mark F ^d   Wilson, Valerie ^b   Semple, Robert K ^e   Sebire, Neil J ^l,m   Kinsler, Veronica A ^l,m   Graupera, Mariona ^f   Vanhaesebroeck, Bart ^a   more..

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF EDINBURGH   (United Kingdom)

^c CNRS   (France)

^d UNIVERSITY COLLEGE LONDON   (United Kingdom)

^e UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^f BELLVITGE BIOMEDICAL RESEARCH INSTITUTE IDIBELL   (Spain)

^g UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^h Medical Research Council Harwell Institute   (United Kingdom)

ⁱ QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^j PETER MACCALLUM CANCER CENTRE   (Australia)

^k UNIVERSITY OF MELBOURNE   (Australia)

^l UNIVERSITY COLLEGE LONDON   (United Kingdom)

^m GREAT ORMOND STREET HOSPITAL   (United Kingdom)

ⁿ UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^o Phylogica Ltd   (Australia)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOPOIETIN RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; RAPAMYCIN; PIK3CA PROTEIN, HUMAN; PIK3CA PROTEIN, MOUSE; TEK PROTEIN, MOUSE;

ADOLESCENT; ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL PROLIFERATION; CHILD; CLINICAL ARTICLE; CONTROLLED STUDY; EMBRYO; ENDOTHELIUM CELL; GENE; GENE EXPRESSION; GENETIC MODEL; HUMAN; MESODERM; MOUSE; MOUSE MODEL; NONHUMAN; PERICYTE; PIK3CA GENE; PRESCHOOL CHILD; PRIORITY JOURNAL; RETINA BLOOD VESSEL; SCHOOL CHILD; SOMATIC MUTATION; TEK GENE; VEIN MALFORMATION; YOUNG ADULT; ANIMAL; C57BL MOUSE; CONGENITAL BLOOD VESSEL MALFORMATION; DRUG EFFECTS; EMBRYOLOGY; ENZYMOLOGY; GENETICS; METABOLISM; MOSAICISM; MUTATION; PATHOLOGY;

ANIMALS; CELL PROLIFERATION; ENDOTHELIAL CELLS; HUMANS; MESODERM; MICE, INBRED C57BL; MOSAICISM; MUTATION; PERICYTES; PHOSPHATIDYLINOSITOL 3-KINASES; RECEPTOR, TIE-2; SIROLIMUS; VASCULAR MALFORMATIONS;

EID: 84962778934     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aad9982     Document Type: Article

References (58)

1. B. Vanhaesebroeck, L. Stephens, P. Hawkins, PI3K signalling: The path to discovery and understanding. Nat. Rev. Mol. Cell Biol. 13, 195-203 (2012).
2. Y. Samuels, Z. Wang, A. Bardelli, N. Silliman, J. Ptak, S. Szabo, H. Yan, A. Gazdar, S. M. Powell, G. J. Riggins, J. K. V. Willson, S. Markowitz, K. W. Kinzler, B. Vogelstein, V. E. Velculescu, High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
3. K. C. Kurek, V. L. Luks, U. M. Ayturk, A. I. Alomari, S. J. Fishman, S. A. Spencer, J. B. Mulliken, M. E. Bowen, G. L. Yamamoto, H. P. W. Kozakewich, M. L. Warman, Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90, 1108-1115 (2012).
4. M. J. Lindhurst, V. E. R. Parker, F. Payne, J. C. Sapp, S. Rudge, J. Harris, A. M. Witkowski, Q. Zhang, M. P. Groeneveld, C. E. Scott, A. Daly, S. M. Huson, L. L. Tosi, M. L. Cunningham, T. N. Darling, J. Geer, Z. Gucev, V. R. Sutton, C. Tziotzios, A. K. Dixon, T. Helliwell, S. O'Rahilly, D. B. Savage, M. J. O. Wakelam, I. Barroso, L. G. Biesecker, R. K. Semple, Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet. 44, 928-933 (2012).
5. J.-B. Rivière, G. M. Mirzaa, B. J. O'Roak, M. Beddaoui, D. Alcantara, R. L. Conway, J. St-Onge, J. A. Schwartzentruber, K. W. Gripp, S. M. Nikkel, T. Worthylake, C. T. Sullivan, T. R. Ward, H. E. Butler, N. A. Kramer, B. Albrecht, C. M. Armour, L. Armstrong, O. Caluseriu, C. Cytrynbaum, B. A. Drolet, A. M. Innes, J. L. Lauzon, A. E. Lin, G. M. S. Mancini, W. S. Meschino, J. D. Reggin, A. K. Saggar, T. Lerman-Sagie, G. Uyanik, R. Weksberg, B. Zirn, C. L. Beaulieu; Finding of Rare Disease Genes (FORGE) Canada Consortium, J. Majewski, D. E. Bulman, M. O'Driscoll, J. Shendure, J. M. Graham Jr., K. M. Boycott, W. B. Dobyns, De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934-940 (2012).
6. J. H. Lee, M. Huynh, J. L. Silhavy, S. Kim, T. Dixon-Salazar, A. Heiberg, E. Scott, V. Bafna, K. J. Hill, A. Collazo, V. Funari, C. Russ, S. B. Gabriel, G. W. Mathern, J. G. Gleeson, De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44, 941-945 (2012).
7. K. M. Keppler-Noreuil, J. J. Rios, V. E. R. Parker, R. K. Semple, M. J. Lindhurst, J. C. Sapp, A. Alomari, M. Ezaki, W. Dobyns, L. G. Biesecker, PIK3CA-related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am. J. Med. Genet. A 167, 287-295 (2015).
8. V. L. Luks, N. Kamitaki, M. P. Vivero, W. Uller, R. Rab, J. V. M. G. Bovée, K. L. Rialon, C. J. Guevara, A. I. Alomari, A. K. Greene, S. J. Fishman, H. P. W. Kozakewich, R. A. Maclellan, J. B. Mulliken, R. Rahbar, S. A. Spencer, C. C. Trenor III, J. Upton, D. Zurakowski, J. A. Perkins, A. Kirsh, J. T. Bennett, W. B. Dobyns, K. C. Kurek, M. L. Warman, S. A. McCarroll, R. Murillo, Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J. Pediatr. 166, 1048-1054.e5 (2015).
9. K. M. Keppler-Noreuil, J. C. Sapp, M. J. Lindhurst, V. E. R. Parker, C. Blumhorst, T. Darling, L. L. Tosi, S. M. Huson, R. W. Whitehouse, E. Jakkula, I. Grant, M. Balasubramanian, K. E. Chandler, J. L. Fraser, Z. Gucev, Y. J. Crow, L. M. Brennan, R. Clark, E. A. Sellars, L. D. M. Pena, V. Krishnamurty, A. Shuen, N. Braverman, M. L. Cunningham, V. R. Sutton, V. Tasic, J. M. Graham Jr., J. Geer Jr., A. Henderson, R. K. Semple, L. G. Biesecker, Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. A 164, 1713-1733 (2014).
10. M. Uebelhoer, L. M. Boon, M. Vikkula, Vascular anomalies: From genetics toward models for therapeutic trials. Cold Spring Harbor Perspect. Med. 2, a009688 (2012).
11. C. E. U. Oduber, V. E. A. Gerdes, C. M. A. M. Van Der Horst, P. Bresser, Vascular malformations as underlying cause of chronic thromboembolism and pulmonary hypertension. J. Plast. Reconstr. Aesthet. Surg. 62, 684-689 (2009).
12. A. Dompmartin, M. Vikkula, L. M. Boon, Venous malformation: Update on aetiopathogenesis, diagnosis and management. Phlebology 25, 224-235 (2010).
13. N. Limaye, V. Wouters, M. Uebelhoer, M. Tuominen, R. Wirkkala, J. B. Mulliken, L. Eklund, L. M. Boon, M. Vikkula, Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat. Genet. 41, 118-124 (2008).
14. M. Natynki, J. Kangas, I. Miinalainen, R. Sormunen, R. Pietilä, J. Soblet, L. M. Boon, M. Vikkula, N. Limaye, L. Eklund, Common and specific effects of TIE2 mutations causing venous malformations. Hum. Mol. Genet. 24, 6374-6389 (2015).
15. P. Castel, F. J. Carmona, J. Grego-Bessa, M. F. Berger, A. Viale, K. V. Anderson, S. Bague, M. Scaltriti, C. R. Antonescu, E. Baselga, J. Baselga, Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci. Transl. Med. 8, 332ra42 (2016).
16. K. M. Kinross, K. G. Montgomery, M. Kleinschmidt, P. Waring, I. Ivetac, A. Tikoo, M. Saad, L. Hare, V. Roh, T. Mantamadiotis, K. E. Sheppard, G. L. Ryland, I. G. Campbell, K. L. Gorringe, J. G. Christensen, C. Cullinane, R. J. Hicks, R. B. Pearson, R. W. Johnstone, G. A. McArthur, W. A. Phillips, An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Invest. 122, 553-557 (2012).
17. H1047R mutation during murine development results in fatal embryonic and extraembryonic defects. Dev. Biol. 404, 14-26 (2015).
18. H. Yamaguchi, T. Niimi, Y. Kitagawa, K. Miki, Brachyury (T) expression in embryonal carcinoma P19 cells resembles its expression in primitive streak and tail-bud but not that in notochord. Dev. Growth Differ. 41, 253-264 (1999).
19. A. Kispert, B. G. Herrmann, Immunohistochemical analysis of the Brachyury protein in wildtype and mutant mouse embryos. Dev. Biol. 161, 179-193 (1994).
20. P. Soriano, Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70-71 (1999).
21. S. Eifert, J. L. Villavicencio, T.-C. Kao, B. M. Taute, N. M. Rich, Prevalence of deep venous anomalies in congenital vascular malformations of venous predominance. J. Vasc. Surg. 31, 462-471 (2000).
22. L. H. Lowe, T. C. Marchant, D. C. Rivard, A. J. Scherbel, Vascular malformations: Classification and terminology the radiologist needs to know. Semin. Roentgenol. 47, 106-117 (2012).
23. J. Soblet, N. Limaye, M. Uebelhoer, L. M. Boon, M. Vikkula, Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol. Syndromol. 4, 179-183 (2013).
24. M. Graupera, J. Guillermet-Guibert, L. C. Foukas, L.-K. Phng, R. J. Cain, A. Salpekar, W. Pearce, S. Meek, J. Millan, P. R. Cutillas, A. J. H. Smith, A. J. Ridley, C. Ruhrberg, H. Gerhardt, B. Vanhaesebroeck, Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662-666 (2008).
25. M. Graupera, M. Potente, Regulation of angiogenesis by PI3K signaling networks. Exp. Cell Res. 319, 1348-1355 (2013).
26. A. Soler, H. Serra, W. Pearce, A. Angulo, J. Guillermet-Guibert, L. S. Friedman, F. Viñals, H. Gerhardt, O. Casanovas, M. Graupera, B. Vanhaesebroeck, Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis. J. Exp. Med. 210, 1937-1945 (2013).
27. B.-H. Jiang, J. Z. Zheng, M. Aoki, P. K. Vogt, Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 97, 1749-1753 (2000).
28. S. Claxton, V. Kostourou, S. Jadeja, P. Chambon, K. Hodivala-Dilke, M. Fruttiger, Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis 46, 74-80 (2008).
29. M. Vikkula, L. M. Boon, K. L. Carraway III, J. T. Calvert, A. J. Diamonti, B. Goumnerov, K. A. Pasyk, D. A. Marchuk, M. L. Warman, L. C. Cantley, J. B. Mulliken, B. R. Olsen, Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87, 1181-1190 (1996).
30. E. R. Andreeva, I. M. Pugach, D. Gordon, A. N. Orekhov, Continuous subendothelial network formed by pericyte-like cells in human vascular bed. Tissue Cell 30, 127-135 (1998).
31. P. Lindahl, B. R. Johansson, P. Levéen, C. Betsholtz, Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242-245 (1997).
32. M. Uebelhoer, M. Nätynki, J. Kangas, A. Mendola, H.-L. Nguyen, J. Soblet, C. Godfraind, L. M. Boon, L. Eklund, N. Limaye, M. Vikkula, Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. Hum. Mol. Genet. 22, 3438-3448 (2013).
33. P. Lindblom, H. Gerhardt, S. Liebner, A. Abramsson, M. Enge, M. Hellström, G. Bäckström, S. Fredriksson, U. Landegren, H. C. Nyström, G. Bergström, E. Dejana, A. Östman, P. Lindahl, C. Betsholtz, Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835-1840 (2003).
34. S. F. Rocha, R. H. Adams, Molecular differentiation and specialization of vascular beds. Angiogenesis 12, 139-147 (2009).
35. D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst, S. H. Snyder, RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35-43 (1994).
36. R. Loewe, D. A. Oble, T. Valero, L. Zukerberg, M. C. Mihm Jr., J. S. Nelson, Stem cell marker upregulation in normal cutaneous vessels following pulsed-dye laser exposure and its abrogation by concurrent rapamycin administration: Implications for treatment of port-wine stain birthmarks. J. Cutan. Pathol. 37(Suppl. 1), 76-82 (2010).
37. S. Kaylani, A. J. Theos, J. G. Pressey, Treatment of infantile hemangiomas with sirolimus in a patient with PHACE syndrome. Pediatr. Dermatol. 30, e194-e197 (2013).
38. H. Yuksekkaya, O. Ozbek, M. Keser, H. Toy, Blue rubber bleb nevus syndrome: Successful treatment with sirolimus. Pediatrics 129, e1080-e1084 (2012).
39. A. M. Hammill, M. Wentzel, A. Gupta, S. Nelson, A. Lucky, R. Elluru, R. Dasgupta, R. G. Azizkhan, D. M. Adams, Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr. Blood Cancer 57, 1018-1024 (2011).
40. S. Riou, E. Morelon, L. Guibaud, F. Chotel, F. Dijoud, P. Marec-Berard, Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. J. Clin. Oncol. 30, e213-e215 (2012).
41. L. Marqués, J. M. Núñez-Córdoba, L. Aguado, M. Pretel, P. Boixeda, E. Nagore, E. Baselga, P. Redondo, Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: Phase II, randomized, double-blind, intraindividual placebo-controlled clinical trial. J. Am. Acad. Dermatol. 72, 151-158.e1 (2015).
42. E. Boscolo, N. Limaye, L. Huang, K.-T. Kang, J. Soblet, M. Uebelhoer, A. Mendola, M. Natynki, E. Seront, S. Dupont, J. Hammer, C. Legrand, C. Brugnara, L. Eklund, M. Vikkul, J. Bischoff, L. M. Boon, Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J. Clin. Invest. 125, 3491-3504 (2015).
43. M. Guba, P. Von Breitenbuch, M. Steinbauer, G. Koehl, S. Flegel, M. Hornung, C. J. Bruns, C. Zuelke, S. Farkas, M. Anthuber, K.-W. Jauch, E. K. Geissler, Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat. Med. 8, 128-135 (2002).
44. C. Chen, Y. Liu, P. Zheng, mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).
45. Y. Fang, R. Westbrook, C. Hill, R. K. Boparai, O. Arum, A. Spong, F. Wang, M. A. Javors, J. Chen, L. Y. Sun, A. Bartke, Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17, 456-462 (2013).
46. Y. A. Wang, J. W. Zheng, Z. L. Fei, X. Q. Jiang, Z. G. Wang, J. Fei, Z. Y. Zhang, A novel transgenic mice model for venous malformation. Transgenic Res. 18, 193-201 (2009).
47. B. Perry, J. Banyard, E. R. McLaughlin, R. Watnick, A. Sohn, D. N. Brindley, T. Obata, L. C. Cantley, C. Cohen, J. L. Arbiser, AKT1 overexpression in endothelial cells leads to the development of cutaneous vascular malformations in vivo. Arch. Dermatol. 143, 504-506 (2007).
48. H1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly. FASEB J. 29, 1426-1434 (2015).
49. T. L. Phung, K. Ziv, D. Dabydeen, G. Eyiah-Mensah, M. Riveros, C. Perruzzi, J. Sun, R. A. Monahan-Earley, I. Shiojima, J. A. Nagy, M. I. Lin, K. Walsh, A. M. Dvorak, D. M. Briscoe, M. Neeman, W. C. Sessa, H. F. Dvorak, L. E. Benjamin, Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10, 159-170 (2006).
50. C. J. Drake, C. D. Little, Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc. Natl. Acad. Sci. U. S. A. 92, 7657-7661 (1995).
51. C. J. Drake, C. D. Little, VEGF and vascular fusion: Implications for normal and pathological vessels. J. Histochem. Cytochem. 47, 1351-1355 (1999).
52. M. Enge, M. Bjarnegård, H. Gerhardt, E. Gustafsson, M. Kalén, N. Asker, H.-P. Hammes, M. Shani, R. Fässler, C. Betsholtz, Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307-4316 (2002).
53. H. U. Wang, Z.-F. Chen, D. J. Anderson, Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753 (1998).
54. M.-J. Yoon, C.-H. Cho, C. S. Lee, I.-H. Jang, S. H. Ryu, G. Y. Koh, Localization of TIE2 and phospholipase D in endothelial caveolae is involved in angiopoietin-1-induced MEK/ERK phosphorylation and migration in endothelial cells. Biochem. Biophys. Res. Commun. 308, 101-105 (2003).
55. I. Kim, H. G. Kim, J.-N. So, J. H. Kim, H. J. Kwak, G. Y. Koh, Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Circ. Res. 86, 24-29 (2000).
56. E. Tzouanacou, S. Tweedie, V. Wilson, Identification of Jade1, a gene encoding a PHD zinc finger protein, in a gene trap mutagenesis screen for genes involved in anteroposterior axis development. Mol. Cell Biol. 23, 8553-8562 (2003).
57. C. Schmidt, V. Wilson, D. Stott, R. S. P. Beddington, T promoter activity in the absence of functional T protein during axis formation and elongation in the mouse. Dev. Biol. 189, 161-173 (1997).
58. M. E. Pitulescu, I. Schmidt, R. Benedito, R. H. Adams, Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. Nat. Protoc. 5, 1518-1534 (2010).