鉴定滤泡性淋巴瘤中 B 细胞淋巴瘤相关基因的 microRNA 结合位点的反复突变。
Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.
机构信息
Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain.
Chinese Institute for Brain Research (CIBR), Beijing 102206, China.
出版信息
Int J Mol Sci. 2020 Nov 20;21(22):8795. doi: 10.3390/ijms21228795.
Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in and genes impaired the binding efficiency of and and regulated the endogenous levels of messenger RNA (mRNA).
滤泡性淋巴瘤 (FL) 是一种常见的惰性 B 细胞淋巴瘤,可转化为侵袭性更强的转化滤泡性淋巴瘤 (tFL)。然而,驱动这种转化的分子过程尚不确定。在这项工作中,我们旨在鉴定滤泡性淋巴瘤患者以及转化滤泡性淋巴瘤患者中反复发生突变的 microRNA (miRNA) 结合位点。使用来自 FL 肿瘤的全基因组测序数据,我们发现了 544 个位于生物信息学预测的 miRNA 结合位点的突变。然后,我们在 55 名 FL 患者的队列中使用靶向测序研究了这些特定区域,发现了 16 个重复突变,并鉴定了另外 69 个变体。经过 QC 过滤,我们确定了 21 个具有突变 miRNA 结合位点的基因,这些基因也通过基因本体富集了 B 细胞相关基因。在这些基因中,超过 40%的突变仅存在于 tFL 患者中。我们通过荧光素酶测定验证了其中 5 个基因的预测 miRNA 结合位点,并证明了 基因和 基因中的鉴定突变降低了 和 的结合效率,并调节了内源性信使 RNA (mRNA) 的水平。