Somatic Activating Variants Cause Isolated Lymphatic Malformations

Overview

Journal HGG Adv

Specialty Genetics

Date 2022 Apr 4

PMID 35373151

Authors

Kaitlyn Zenner

Dana M Jensen

Victoria Dmyterko

Giridhar M Shivaram

Candace T Myers

Cate R Paschal

Erin R Rudzinski

Minh-Hang M Pham

V Chi Cheng

Scott C Manning

Randall A Bly

Sheila Ganti

Jonathan A Perkins

James T Bennett

Affiliations

Soon will be listed here.

Abstract

Somatic activating variants in , the gene that encodes the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in ∼80% of lymphatic malformations (LMs). We report the presence of somatic activating variants in in individuals with LMs that do not possess pathogenic variants. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LMs. Histology revealed abnormal lymphatic channels with immunopositivity for BRAF in endothelial cells that was otherwise indistinguishable from -positive LM. The finding that variants contribute to low-flow LMs increases the complexity of prior models associating low-flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high-flow vascular malformations (arteriovenous malformations) with mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. In addition, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.

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