GENETIC LANDSCAPE OF COMMON VENOUS MALFORMATIONS IN THE HEAD AND NECK.

ABSTRACT Objective Common venous malformations are a frequent sporadic subtype of vascular malformations. Given the TEK and PIK3CA mutations identified, this study aims to investigate the genetic landscape of venous malformations in the head and neck. Methods Patients from published sequencing studies related to common venous malformations were reviewed. Detailed data regarding clinical characteristics, sequencing strategies and mutation frequency were synthesized. Lesion distribution of common venous malformations in the head and neck were further retrospectively analyzed by the pathological database of the Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital. For the frequently affected sites in the head and neck, patients were selected for targeted sequencing with a designed vascular malformation–related gene panel or whole‐exome sequencing. Detected variants were analyzed by classical bioinformatic algorithms (SIFT23, PolyPhen-2 HDIV, LRT, MutationTaster, Mutation Assessor, and GERP++). To confirm the expression pattern of particular candidate gene, specimens were examined histochemically. Gene Ontology enrichment analysis, protein-protein interaction network was also constructed. Results Three hundred patients from 8 sequencing studies related to common VMs were reviewed. The total prevalence rates of TEK/PIK3CA mutations were 41.3%/26.7%. The most frequent TEK/PIK3CA mutations were TEK-L914F/PIK3CA-H1047R. TEK/PIK3CA mutations existed in 70.3%/2.7% of venous malformations in the head and neck. In retrospective data from 649 patients carrying cervicofacial venous malformations at Shanghai Ninth Hospital, the most frequent sites were the maxillofacial region (lips, cheek, parotid–masseteric region, submandibular region) and the oral and oropharyngeal region (buccal mucosa, tongue). Targeted sequencing for 14 frequent lesions detected TEK variants in 3 patients (21.4%) but no PIK3CA mutations. On whole-exome sequencing of 2 patients without TEK/PIK3CA mutations, CDH11 was the only shared deleteriously mutated gene. Bioinformatic analyses of CDH11 implied that genes involved in cellular adhesion and junctions formed a significant portion. Conclusions: Common venous malformations of the head and neck have a unique genetic landscape. Novel CDH11 and TEK variants imply that pathogenesis is mediated by the regulatory relationship between endothelial cells and extracellular components.