Barclay et al published an article in the Journal Genetics in Medicine and we got permission from the author to share a link on our website.
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. They hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development.
Barclay et al performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. They used digital polymerase chain reaction (dPCR) to validate the exome findings and to screen KLA samples from six other individuals.
Barclay et al identified a somatic activating NRAS variant (c.182A>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.
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 NRAS pathway inhibitors.