Whole transcriptome sequencing detects a large number of novel fusion transcripts in patients with AML and MDS
Whole transcriptome sequencing detects a large number of novel fusion transcripts in patients with AML and MDS
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DOI：
10.1182/bloodadvances.2020003007
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发表时间：
2020-11-10
期刊：
影响因子：
7.5
通讯作者：
Haferlach, Claudia
中科院分区：
文献类型：
--
作者：
Stengel, Anna;Shahswar, Rabia;Haferlach, Claudia
融合转录本是骨髓恶性肿瘤中常见的遗传异常，通常是风险分层、微小残留病 (MRD) 监测和靶向治疗的基础。我们通过全转录组测序 (WTS) 全面分析了 572 名急性髓系白血病 (AML) 和 630 名骨髓增生异常综合征 (MDS) 患者的融合转录物情况。总共，在 210/572 名 AML 患者 (37%) 中发现了 274 个融合事件（131 个独特的融合）。在 16/630 名 MDS 患者中，检测到 16 个融合事件（15 个独特的融合）（3%）。在 AML 中，141 例包含实体定义重排（占所有检测到的融合的 51%）和 21 例（8%）其他众所周知的融合，全部由 WTS（对照组）检测到。在 MDS 中，之前仅描述了 1 个融合（NRIP1-MECOM，n = 2）。有趣的是，迄今为止发现了大量未报告的融合（AML 中 41% [112/274]，MDS 中 88% [14/16]），所有这些都通过细胞遗传学和/或全基因组测序数据进行了验证。除 1 例例外（CTDSP1-CFLAR，n = 2）外，所有新融合均在 1 名患者中观察到。在 AML 中，具有新融合的病例同时表现出高频率的 TP53 突变（67%）和复杂核型（71%），这在 MDS 中也观察到，但不太明显（TP53，26%；复杂核型，21%）。参与新型融合的基因的功能注释揭示了许多功能相关基因（例如转录因子；AML 中 n = 28，MDS 中 n = 2）或酶（AML 中 n = 42，MDS 中 n = 9）。总而言之，导致融合转录本的新基因组改变在 AML 中比在 MDS 中更为常见。任何新的融合都可能用于开发标记（例如，用于 MRD 监测），特别是在没有实体定义异常的情况下。
Fusion transcripts are frequent genetic abnormalities in myeloid malignancies and are often the basis for risk stratification, minimal residual disease (MRD) monitoring, and targeted therapy. We comprehensively analyzed the fusion transcript landscape in 572 acute myeloid leukemia (AML) and 630 myelodysplastic syndrome (MDS) patients by whole transcriptome sequencing (WTS). Totally, 274 fusion events (131 unique fusions) were identified in 210/572 AML patients (37%). In 16/630 MDS patients, 16 fusion events (15 unique fusions) were detected (3%). In AML, 141 cases comprised entity-defining rearrangements (51% of all detected fusions) and 21 (8%) additional well-known fusions, all detected by WTS (control group). In MDS, only 1 fusion was described previously (NRIP1-MECOM, n = 2). Interestingly, a high number of so-far unreported fusions were found (41% [112/274] in AML, 88% [14/16] in MDS), all validated by cytogenetic and/or whole genome sequencing data. With 1 exception (CTDSP1-CFLAR, n = 2), all novel fusions were observed in 1 patient each. In AML, cases with novel fusions showed concomitantly a high frequency of TP53 mutations (67%) and of a complex karyotype (71%), which was also observed in MDS, but less pronounced (TP53, 26%; complex karyotype, 21%). A functional annotation of genes involved in novel fusions revealed many functional relevant genes (eg, transcription factors; n = 28 in AML, n = 2 in MDS) or enzymes (n = 42 in AML, n = 9 in MDS). Taken together, new genomic alterations leading to fusion transcripts were much more common in AML than in MDS. Any novel fusions might be of use for developing markers (eg, for MRD monitoring), particularly in cases without an entity-defining abnormality.