A somatic activating NRAS variant associated with kaposiform lymphangiomatosis
| Autor: | Cameron C. Trenor, Harry P.W. Kozakewich, Alyaa Al-Ibraheemi, Kyle C. Kurek, Denise M. Adams, Lori Walker, Antonio R. Perez-Atayde, Steven J. Fishman, Gulraiz Chaudry, Ahmad I. Alomari, Shamlal Mangray, Sara R Kreimer, Sarah F. Barclay, John B. McIntyre, Michael Jeng, Kyle W Inman, Alanna J. Church, Valerie L. Luks |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Neuroblastoma RAS viral oncogene homolog Adolescent lymphatic malformation Somatic cell Polymerase Chain Reaction vascular anomaly Article GTP Phosphohydrolases high throughput sequencing Vascular anomaly 03 medical and health sciences 0302 clinical medicine 030225 pediatrics Exome Sequencing medicine Humans Child Lymphatic Diseases Exome Lymphangiomatosis Genetics (clinical) Exome sequencing PI3K/AKT/mTOR pathway business.industry Melanoma Genetic Variation Infant Membrane Proteins medicine.disease 3. Good health 030104 developmental biology Child Preschool Cancer research Female business Mosaic |
| Zdroj: | Genetics in medicine : official journal of the American College of Medical Genetics |
| ISSN: | 1098-3600 |
| Popis: | 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 PCR (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. Results: We identified a somatic activating NRAS variant (c.182A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1–28%, 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 signalling pathways. This discovery will expand treatment options for these high risk patients as there is potential for use of targeted RAS pathway inhibitors. |
| Databáze: | OpenAIRE |
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