Sorbonne Université, Département de génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
Department of Pathology, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
J Eur Acad Dermatol Venereol. 2022 Jun;36(6):905-912. doi: 10.1111/jdv.18046. Epub 2022 Mar 11.
Somatic genetic variants may be the cause of extracranial arteriovenous malformations, but few studies have explored these genetic anomalies, and no genotype-phenotype correlations have been identified.
The aim of the study was to characterize the somatic genetic landscape of extracranial arteriovenous malformations and correlate these findings with the phenotypic characteristics of these lesions.
This study included twenty-three patients with extracranial arteriovenous malformations that were confirmed clinically and treated by surgical resection, and for whom frozen tissue samples were available. Targeted next-generation sequencing analysis of tissues was performed using a gene panel that included vascular disease-related genes and tumour-related genes.
We identified a pathogenic variant in 18 out of 23 samples (78.3%). Pathogenic variants were mainly located in MAP2K1 (n = 7) and KRAS (n = 6), and more rarely in BRAF (n = 2) and RASA1 (n = 3). KRAS variants were significantly (P < 0.005) associated with severe extended facial arteriovenous malformations, for which relapse after surgical resection is frequently observed, while MAP2K1 variants were significantly (P < 0.005) associated with less severe, limited arteriovenous malformations located on the lips.
Our study highlights a high prevalence of pathogenic somatic variants, predominantly in MAP2K1 and KRAS, in extracranial arteriovenous malformations. In addition, our study identifies for the first time a correlation between the genotype, clinical severity and angiographic characteristics of extracranial arteriovenous malformations. The RAS/MAPK variants identified in this study are known to be associated with malignant tumours for which targeted therapies have already been developed. Thus, identification of these somatic variants could lead to new therapeutic options to improve the management of patients with extracranial arteriovenous malformations.
体细胞遗传变异可能是颅外动静脉畸形的病因，但很少有研究探索这些遗传异常，也没有确定基因型-表型相关性。
本研究旨在描述颅外动静脉畸形的体细胞遗传特征，并将这些发现与这些病变的表型特征相关联。
本研究纳入了 23 例经临床和手术切除证实的颅外动静脉畸形患者，且这些患者有冷冻组织样本可用。采用包含血管疾病相关基因和肿瘤相关基因的基因面板对组织进行靶向下一代测序分析。
我们在 23 个样本中的 18 个（78.3%）中发现了致病性变异。致病性变异主要位于 MAP2K1（n=7）和 KRAS（n=6），较少位于 BRAF（n=2）和 RASA1（n=3）。KRAS 变异与严重的广泛面部动静脉畸形显著相关（P<0.005），这种畸形手术后常复发，而 MAP2K1 变异与位于唇部的不太严重、局限的动静脉畸形显著相关（P<0.005）。
本研究强调了颅外动静脉畸形中致病性体细胞变异的高发生率，主要是在 MAP2K1 和 KRAS 中。此外，本研究首次确定了颅外动静脉畸形的基因型、临床严重程度和血管造影特征之间的相关性。本研究中鉴定的 RAS/MAPK 变异与已开发出靶向治疗的恶性肿瘤相关。因此，鉴定这些体细胞变异可能会为改善颅外动静脉畸形患者的管理提供新的治疗选择。
