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A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

ABSTRACT: PURPOSE:Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. METHODS:We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. RESULTS:We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues. CONCLUSION:The activating NRAS p.Q61R variant is a known "hotspot" variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways. This discovery will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.

SUBMITTER: Barclay SF

PROVIDER: S-EPMC6565516 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

Barclay Sarah F SF Inman Kyle W KW Luks Valerie L VL McIntyre John B JB Al-Ibraheemi Alyaa A Church Alanna J AJ Perez-Atayde Antonio R AR Mangray Shamlal S Jeng Michael M Kreimer Sara R SR Walker Lori L Fishman Steven J SJ Alomari Ahmad I AI Chaudry Gulraiz G Trenor Iii Cameron C CC Adams Denise D Kozakewich Harry P W HPW Kurek Kyle C KC

Genetics in medicine : official journal of the American College of Medical Genetics 20181213 7

<h4>Purpose</h4>Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development.<h4>Methods</h4>We performed exom ...[more]

PMID: 30542204

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Project description:BackgroundKaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.MethodsThe NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.ResultsTrametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.ConclusionsTrametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.ImpactThis is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

Dataset Information

A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

Publications

A somatic activating NRAS variant associated with kaposiform lymphangiomatosis.

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