Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

Lara Rodriguez‑Laguna; Noelia Agra; Kristina Ibañez; Gloria Oliva‑Molina; Gema Gordo; Noor Khurana; Devon Hominick; María Beato; Isabel Colmenero; Gonzalo Herranz; Juan M. Torres Canizalez; Rebeca Rodríguez Pena; Elena Vallespín; Rubén Martín‑Arenas; Ángela Del Pozo; Cristina Villaverde; Ana Bustamante; Carmen Ayuso; Pablo Lapunzina; Juan C. Lopez‑Gutierrez; Michael T. Dellinger; Victor Martinez‑Glez

doi:10.1084/jem.20181353

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

Lara Rodriguez‑Laguna, Noelia Agra, Kristina Ibañez, Gloria Oliva‑Molina, Gema Gordo, Noor Khurana, Devon Hominick, María Beato, Isabel Colmenero, Gonzalo Herranz, Juan M. Torres Canizalez, Rebeca Rodríguez Pena, Elena Vallespín, Rubén Martín‑Arenas, Ángela Del Pozo, Cristina Villaverde, Ana Bustamante, Carmen Ayuso, Pablo Lapunzina, Juan C. Lopez‑GutierrezMichael T. Dellinger, Victor Martinez‑Glez

Research output: Contribution to journal › Article › peer-review

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Abstract

Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

Original language	English (US)
Pages (from-to)	407-418
Number of pages	12
Journal	Journal of Experimental Medicine
Volume	216
Issue number	2
DOIs	https://doi.org/10.1084/jem.20181353
State	Published - Feb 1 2019

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/jem.20181353

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Rodriguez‑Laguna, L., Agra, N., Ibañez, K., Oliva‑Molina, G., Gordo, G., Khurana, N., Hominick, D., Beato, M., Colmenero, I., Herranz, G., Torres Canizalez, J. M., Pena, R. R., Vallespín, E., Martín‑Arenas, R., Del Pozo, Á., Villaverde, C., Bustamante, A., Ayuso, C., Lapunzina, P., ... Martinez‑Glez, V. (2019). Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. Journal of Experimental Medicine, 216(2), 407-418. https://doi.org/10.1084/jem.20181353

Rodriguez‑Laguna, L, Agra, N, Ibañez, K, Oliva‑Molina, G, Gordo, G, Khurana, N, Hominick, D, Beato, M, Colmenero, I, Herranz, G, Torres Canizalez, JM, Pena, RR, Vallespín, E, Martín‑Arenas, R, Del Pozo, Á, Villaverde, C, Bustamante, A, Ayuso, C, Lapunzina, P, Lopez‑Gutierrez, JC, Dellinger, MT & Martinez‑Glez, V 2019, 'Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly', Journal of Experimental Medicine, vol. 216, no. 2, pp. 407-418. https://doi.org/10.1084/jem.20181353

@article{1b57665d6637448fa0ca3368631b1b8c,

title = "Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly",

abstract = "Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.",

author = "Lara Rodriguez‑Laguna and Noelia Agra and Kristina Iba{\~n}ez and Gloria Oliva‑Molina and Gema Gordo and Noor Khurana and Devon Hominick and Mar{\'i}a Beato and Isabel Colmenero and Gonzalo Herranz and {Torres Canizalez}, {Juan M.} and Pena, {Rebeca Rodr{\'i}guez} and Elena Vallesp{\'i}n and Rub{\'e}n Mart{\'i}n‑Arenas and {Del Pozo}, {\'A}ngela and Cristina Villaverde and Ana Bustamante and Carmen Ayuso and Pablo Lapunzina and Lopez‑Gutierrez, {Juan C.} and Dellinger, {Michael T.} and Victor Martinez‑Glez",

note = "Funding Information: We thank all patients and their families for their participation in this study. This work was funded by The Lymphatic Malformation Institute (Ref. PI-1404). The authors declare no competing financial interests. Author contributions: P. Lapunzina, J.C. Lopez-Gutierrez, and V. Martinez-Glez designed and supervised the study. L. Rodriguez-Laguna, M.T. Dellinger, and V. Martinez-Glez wrote the manuscript. C. Ayuso critically revised the study and the manuscript for intellectual content. N. Agra, G. Oliva-Molina, and G. Herranz performed in vitro cellular studies. J.M. Torres Canizalez and R. Rodr{\'i}guez Pena designed and supervised flow cytom-etry experiments. L. Rodriguez-Laguna and N. Agra participated in the draft of the manuscript. P. Lapunzina, J.C. Lopez-Gutierrez, and V. Martinez-Glez evaluated patients and collaborated in the clinical characterization of the patients. M. Beato and I. Colmenero performed histopathological studies. E. Vallesp{\'i}n supervised and R. Mart{\'i}n-Arenas performed the high-throughput sequencing experiments. A. Bustamante supervised and C. Villaverde, G. Gordo, and L. Rodriguez-Laguna performed ddPCR experiments. K. Iba{\~n}ez, A. del Pozo, and L. Rodriguez-Laguna performed the bioinformatic analysis, and L. Rodriguez-Laguna, G. Gordo, K. Iba{\~n}ez, and A. del Pozo developed the in-house bioinformatic pipelines for low-mosaics detection. G. Gordo and L. Rodriguez-Laguna performed molecular experiments and analysis other than high-throughput sequencing (Sanger sequencing, pyrosequencing, etc.). N. Khurana, D. Hominick, and M.T. Dellinger performed animal studies. All authors have approved the manuscript for submission. Funding Information: This work was funded by The Lymphatic Malformation Institute (Ref. PI-1404). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2018 Rodriguez‑Laguna et al.",

year = "2019",

month = feb,

day = "1",

doi = "10.1084/jem.20181353",

language = "English (US)",

volume = "216",

pages = "407--418",

journal = "Journal of Experimental Medicine",

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TY - JOUR

T1 - Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

AU - Rodriguez‑Laguna, Lara

AU - Agra, Noelia

AU - Ibañez, Kristina

AU - Oliva‑Molina, Gloria

AU - Gordo, Gema

AU - Khurana, Noor

AU - Hominick, Devon

AU - Beato, María

AU - Colmenero, Isabel

AU - Herranz, Gonzalo

AU - Torres Canizalez, Juan M.

AU - Pena, Rebeca Rodríguez

AU - Vallespín, Elena

AU - Martín‑Arenas, Rubén

AU - Del Pozo, Ángela

AU - Villaverde, Cristina

AU - Bustamante, Ana

AU - Ayuso, Carmen

AU - Lapunzina, Pablo

AU - Lopez‑Gutierrez, Juan C.

AU - Dellinger, Michael T.

AU - Martinez‑Glez, Victor

N1 - Funding Information: We thank all patients and their families for their participation in this study. This work was funded by The Lymphatic Malformation Institute (Ref. PI-1404). The authors declare no competing financial interests. Author contributions: P. Lapunzina, J.C. Lopez-Gutierrez, and V. Martinez-Glez designed and supervised the study. L. Rodriguez-Laguna, M.T. Dellinger, and V. Martinez-Glez wrote the manuscript. C. Ayuso critically revised the study and the manuscript for intellectual content. N. Agra, G. Oliva-Molina, and G. Herranz performed in vitro cellular studies. J.M. Torres Canizalez and R. Rodríguez Pena designed and supervised flow cytom-etry experiments. L. Rodriguez-Laguna and N. Agra participated in the draft of the manuscript. P. Lapunzina, J.C. Lopez-Gutierrez, and V. Martinez-Glez evaluated patients and collaborated in the clinical characterization of the patients. M. Beato and I. Colmenero performed histopathological studies. E. Vallespín supervised and R. Martín-Arenas performed the high-throughput sequencing experiments. A. Bustamante supervised and C. Villaverde, G. Gordo, and L. Rodriguez-Laguna performed ddPCR experiments. K. Ibañez, A. del Pozo, and L. Rodriguez-Laguna performed the bioinformatic analysis, and L. Rodriguez-Laguna, G. Gordo, K. Ibañez, and A. del Pozo developed the in-house bioinformatic pipelines for low-mosaics detection. G. Gordo and L. Rodriguez-Laguna performed molecular experiments and analysis other than high-throughput sequencing (Sanger sequencing, pyrosequencing, etc.). N. Khurana, D. Hominick, and M.T. Dellinger performed animal studies. All authors have approved the manuscript for submission. Funding Information: This work was funded by The Lymphatic Malformation Institute (Ref. PI-1404). The authors declare no competing financial interests. Publisher Copyright: © 2018 Rodriguez‑Laguna et al.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

AB - Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

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U2 - 10.1084/jem.20181353

DO - 10.1084/jem.20181353

M3 - Article

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SP - 407

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JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 2

ER -

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

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