Accurate calling of KIAA1549‐BRAF fusions from DNA of human brain tumours using methylation array‐based copy number and gene panel sequencing data,Neuropathology and Applied Neurobiology

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Accurate calling of KIAA1549‐BRAF fusions from DNA of human brain tumours using methylation array‐based copy number and gene panel sequencing data
Neuropathology and Applied Neurobiology ( IF 4.0 ) Pub Date : 2021-01-17 , DOI: 10.1111/nan.12683
Damian Stichel _{1,

2} , Daniel Schrimpf _{1,

2} , Philipp Sievers _{1,

2} , Annekathrin Reinhardt _{1,

2} , Abigail K Suwala _{1,

2} , Martin Sill _{3,

4} , David E Reuss _{1,

2} , Andrey Korshunov _{1,

2,

3} , Belén M Casalini _{1,

2} , Alexander C Sommerkamp _{3,

5,

6} , Jonas Ecker _{3,

7,

8} , Florian Selt _{3,

7,

8} , Dominik Sturm _{3,

5,

7} , Astrid Gnekow ₉ , Arend Koch _{10,

11} , Michèle Simon ₁₂ , Pablo Hernáiz Driever ₁₂ , Ulrich Schüller _{13,

14,

15} , David Capper _{10,

11} , Cornelis M van Tilburg _{3,

7,

8} , Olaf Witt _{3,

7,

8} , Till Milde _{3,

7,

8} , Stefan M Pfister _{3,

4,

7} , David T W Jones _{3,

5} , Andreas von Deimling _{1,

2} , Felix Sahm _{1,

2,

3} , Annika K Wefers _{1,

2,

3,

13,

14,

15}

Affiliation

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.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
Swabian Children's Cancer Center, University Hospital Augsburg, Augsburg, Germany.
Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
German Cancer Consortium (DKTK, Partner Site Berlin, German Cancer Research Center (DKFZ, Heidelberg, Germany.
Department of Pediatric Oncology/Hematology and Stem Cell Transplantation, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.

AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

使用基于甲基化阵列的拷贝数和基因组测序数据从人脑肿瘤的 DNA 中准确调用 KIAA1549-BRAF 融合

AIMS KIAA1549-BRAF 融合发生在某些脑肿瘤中，并且由于 MAP 激酶途径的组成型激活而提供可药物靶点。我们介绍了从 DNA 甲基化阵列衍生的拷贝数以及 DNA 面板测序数据调用 KIAA1549-BRAF 融合的工作流程。方法通过自动筛选和目视验证染色体 7q34 上的串联重复来分析拷贝数谱，表明 KIAA1549-BRAF 融合。具有已知融合状态的 ICGC 队列的毛细胞星形细胞瘤用于验证。KIAA1549-BRAF 融合是使用融合调用程序 Manta、Arriba 和修改后的过滤标准和 deFuse 从 DNA 面板测序数据中调用的。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。结果我们利用 DNA 甲基化和面板测序数据确定了 337 个脑肿瘤的融合。其中，我们使用带有改良过滤器的 Arriba 从 84% 的拷贝数数据和超过 90% 的 DNA 面板测序数据中检测到融合。虽然 74% 的 KIAA1549-BRAF 融合是从甲基化阵列衍生的拷贝数和面板测序数据中检测到的，但 9% 仅从拷贝数数据中检测到，16% 仅从面板数据中检测到。这种融合几乎只见于毛细胞星形细胞瘤、弥漫性软脑膜胶质神经元肿瘤和具有毛状特征的高级别星形细胞瘤。结论 KIAA1549-BRAF 融合可以从 DNA 甲基化阵列或 DNA 面板数据中可靠地检测到。

更新日期：2021-01-17

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