Purpose

Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM.

Methods

cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital polymerase chain reaction (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay.

Results

Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5).

Conclusion

Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients, which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.

中文翻译：

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游离 DNA 作为血管畸形分子诊断的诊断分析物。

目的

血管畸形 (VM) 主要由体细胞激活致癌基因中的致病变异引起。靶向药物疗法正在兴起，但需要分子诊断。由于目前仅在畸形组织中检测到变异，因此患者可能没有资格在手术前进行临床试验。我们假设无细胞 DNA (cfDNA) 可以为孤立性 VM 患者提供分子诊断。

方法

从动静脉畸形 (AVM)、静脉畸形 (VeM) 或淋巴畸形 (LM) 患者的血浆或囊液中分离出 cfDNA，并使用液滴数字聚合酶链反应 (ddPCR) 检测已知的致病变异。使用多重 ddPCR 分析前瞻性地筛选来自独立 LM 患者队列的囊液 cfDNA 的变异。

结果

在 AVM (2/8) 和 VeM (1/3) 患者的血浆 cfDNA 中检测到变异。在 LM 患者的囊液 cfDNA (7/7) 中检测到变异，但在血浆 (0/26) 中未检测到。使用多重 ddPCR 对囊液 cfDNA 的前瞻性测试发现了从未接受过手术的 LM 患者的变异 (4/5)。

结论

在 AVM 和 VeM 患者的血浆以及 LM 患者的囊液中检测到变异。这些数据支持对 VM 患者基于 cfDNA 的分子诊断的研究，这可能为无需事先手术即可启动靶向药物治疗提供机会。