Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Neuropathol Appl Neurobiol. 2021 Apr;47(3):406-414. doi: 10.1111/nan.12683. Epub 2021 Jan 17.
KIAA1549-BRAF fusions occur in certain brain tumours and provide druggable targets due to a constitutive activation of the MAP-kinase pathway. We introduce workflows for calling the KIAA1549-BRAF fusion from DNA methylation array-derived copy number as well as DNA panel sequencing data.
Copy number profiles were analysed by automated screening and visual verification of a tandem duplication on chromosome 7q34, indicative of the KIAA1549-BRAF fusion. Pilocytic astrocytomas of the ICGC cohort with known fusion status were used for validation. KIAA1549-BRAF fusions were called from DNA panel sequencing data using the fusion callers Manta, Arriba with modified filtering criteria and deFuse. We screened DNA methylation and panel sequencing data of 7790 specimens from brain tumour and sarcoma entities.
We identified the fusion in 337 brain tumours with both DNA methylation and panel sequencing data. Among these, we detected the fusion from copy number data in 84% and from DNA panel sequencing data in more than 90% using Arriba with modified filters. While in 74% the KIAA1549-BRAF fusion was detected from both methylation array-derived copy number and panel sequencing data, in 9% it was detected from copy number data only and in 16% from panel data only. The fusion was almost exclusively found in pilocytic astrocytomas, diffuse leptomeningeal glioneuronal tumours and high-grade astrocytomas with piloid features.
The KIAA1549-BRAF fusion can be reliably detected from either DNA methylation array or DNA panel data. The use of both methods is recommended for the most sensitive detection of this diagnostically and therapeutically important marker.
KIAA1549-BRAF 融合发生在某些脑肿瘤中，并由于 MAP 激酶途径的组成性激活提供了可药物靶向的目标。我们介绍了从 DNA 甲基化阵列衍生的拷贝数以及 DNA 面板测序数据中调用 KIAA1549-BRAF 融合的工作流程。
通过自动筛选和对 7q34 染色体上串联重复的视觉验证来分析拷贝数谱，这表明存在 KIAA1549-BRAF 融合。使用融合状态已知的 ICGC 队列中的毛细胞星形细胞瘤进行验证。使用融合调用器 Manta、Arriba（带有修改的过滤标准）和 deFuse 从 DNA 面板测序数据中调用 KIAA1549-BRAF 融合。我们筛选了来自脑肿瘤和肉瘤实体的 7790 个样本的 DNA 甲基化和面板测序数据。
我们在具有 DNA 甲基化和面板测序数据的 337 个脑肿瘤中鉴定出了融合。在这些肿瘤中，我们使用修改后的过滤器在 Arriba 中从 84%的拷贝数数据中检测到融合，从超过 90%的 DNA 面板测序数据中检测到融合。在 74%的情况下，从甲基化阵列衍生的拷贝数和面板测序数据中都检测到了 KIAA1549-BRAF 融合，在 9%的情况下仅从拷贝数数据中检测到融合，在 16%的情况下仅从面板数据中检测到融合。该融合几乎仅在毛细胞星形细胞瘤、弥漫性软脑膜神经胶质细胞瘤和具有多形性特征的高级别星形细胞瘤中发现。
可以从 DNA 甲基化阵列或 DNA 面板数据中可靠地检测到 KIAA1549-BRAF 融合。为了最敏感地检测到这个具有诊断和治疗意义的标志物，建议同时使用这两种方法。
