Lymphatic and Other Vascular Malformative/Overgrowth Disorders Are Caused by Somatic Mutations in PIK3CA - 26/03/15

Doi : 10.1016/j.jpeds.2014.12.069

Valerie L. Luks, BS ^1,^{^{∗
Contributed equally.}}, Nolan Kamitaki ^2,^{^{∗
Contributed equally.}}, Matthew P. Vivero, BA ¹, Wibke Uller, MD ¹, Rashed Rab, BA ³, Judith V.M.G. Bovée, MD, PhD ⁴, Kristy L. Rialon, MD ¹, Carlos J. Guevara, MD ¹, Ahmad I. Alomari, MD ¹, Arin K. Greene, MD, MMSc ¹, Steven J. Fishman, MD ¹, Harry P.W. Kozakewich, MD ¹, Reid A. Maclellan, MD, MMSc ¹, John B. Mulliken, MD ¹, Reza Rahbar, MD ¹, Samantha A. Spencer, MD ¹, Cameron C. Trenor, MD ¹, Joseph Upton, MD ¹, David Zurakowski, PhD ¹, Jonathan A. Perkins, DO ⁵, Andrew Kirsh, PhD ⁵, James T. Bennett, MD, PhD ⁵, William B. Dobyns, MD ⁵, Kyle C. Kurek, MD, MMSc ¹, Matthew L. Warman, MD ^1,^2,^3,^⁎ , Steven A. McCarroll, PhD ², Rudy Murillo, MD ¹
¹ Vascular Anomalies Center, Boston Children's Hospital, Boston, MA
² Department of Genetics, Harvard Medical School, Boston, MA
³ Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA
⁴ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
⁵ Departments of Pediatrics and Surgery, University of Washington, Seattle, WA

^∗Reprint requests: Rudy Murillo, MD or Matthew L. Warman, MD, Boston Children's Hospital, EN250, 320 Longwood Ave, Boston, MA 02115.

Abstract

Objectives

To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS).

Study design

We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital.

Results

Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells.

Conclusions

Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low.

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Keyword : CLOVES, ddPCR, FAVA, FFPE, KTS, LM, NGS, PCR, PI3K, PIK3CA, smMIP, TCS, WES

Plan

Genotype-Phenotype Association

Results

Discussion

Supported by the Manton Center for Orphan Disease Research at Boston Children's Hospital, the Stuart and Jane Weitzman Fund for Vascular Anomalies Research at Boston Children's Hospital, the Howard Hughes Medical Institute, and the National Institutes of Health (AR064231). The authors declare no conflicts of interest.

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Vol 166 - N° 4

P. 1048 - avril 2015 Retour au numéro

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Lymphatic and Other Vascular Malformative/Overgrowth Disorders Are Caused by Somatic Mutations in PIK3CA - 26/03/15

Abstract

Objectives

Study design

Results

Conclusions

Plan

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