Mutational profile and mutational burden of resected Sporadic Brain Arteriovenous Malformations analyzed through Next-generation Sequencing: a retrospective series.

Introduction: Sporadic brain arteriovenous malformations (bAVMs) may be caused by abnormal signaling in the vascular endothelial growth factor pathway, resulting in aberrant angiogenesis. Next-generation sequencing (NGS) allows to massively sequence the DNA in a short time. A large NGS analysis of bAVMS could aid in the discovery of novel genes and variants with predictive and prognostic value as well as potential therapeutic targets.
The current understanding of the molecular biology of bAVMs is limited. Our aim was to comprehensively study the mutational profile (MP) and mutational burden (MB) of resected bAVMs to search for potential actionable alterations.

Methods: A retrospective series of six consecutively resected sporadic bAVMs was analyzed. Paraffin-embedded tissue sections were used for DNA extraction and quantification. The DNA libraries were analyzed using the Oncomine Tumor Mutational Load Assay, that covers the sequence of 392 genes commonly altered in cancer, to inform of the MP and MB of each of the samples analyzed.

Results: The specimens harbored a total of 2306 variants. Among the six cases four revealed at least one known pathological mutation. Among these four cases, missense mutations in KRAS (p.Gly12Asp), nonsense mutations in CDK12 (p.Gln696Ter), frameshift insertion of ERCC2 (p.Ala600SerfsTer50), and in-frame deletion of FGFR1 (p.Asp166del), MYC (p.Gln52del), and Notch 1 (p.Pro2415del) were detected. While, most case showed a low MB ( < 2), the KRAS-mutant case showed a MB of 20.08 mutations per megabase (muts/Mb), and another case had 9.24 muts/Mb.

Conclusion : NGS can help to better understand the genetic alterations and molecular pathways that underly bAVMs possibly allowing for the development of targeted treatments that could improve the prognosis of patients with bAVMs.