Somatic activating BRAF variants cause isolated lymphatic malformations

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

doi:10.1016/j.xhgg.2022.100101

Somatic activating BRAF variants cause isolated lymphatic malformations

HGG Adv. 2022 Mar 15;3(2):100101. doi: 10.1016/j.xhgg.2022.100101. eCollection 2022 Apr 14.

Authors

Kaitlyn Zenner^{1

2}, Dana M Jensen³, Victoria Dmyterko³, Giridhar M Shivaram⁴, Candace T Myers⁵, Cate R Paschal⁵, Erin R Rudzinski⁵, Minh-Hang M Pham⁶, V Chi Cheng⁶, Scott C Manning¹, Randall A Bly^{1

2}, Sheila Ganti^{1

2

7}, Jonathan A Perkins^{1

2}, James T Bennett^{2

3

8}

Affiliations

¹ Seattle Children's Hospital, Division of Pediatric Otolaryngology, Department of Otolaryngology/Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA.
² Vascular Anomalies Program, Seattle Children's Hospital, Seattle, WA 98105, USA.
³ Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁴ Department of Radiology, Division of Interventional Radiology, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA.
⁶ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁷ Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁸ Seattle Children's Hospital, Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Abstract

Somatic activating variants in PIK3CA, the gene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in ∼80% of lymphatic malformations (LMs).¹ ^, ² We report the presence of somatic activating variants in BRAF in individuals with LMs that do not possess pathogenic PIK3CA 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^V600E in endothelial cells that was otherwise indistinguishable from PIK3CA-positive LM. The finding that BRAF 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.³ 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.

Keywords: BRAF; PIK3CA; VANSeq; clinical diagnostics; ddPCR; endothelium; lymphatic malformation; mosaicism; post-zygotic; vascular.