Whole-genome landscape of adult T-cell leukemia/lymphoma
Whole-genome landscape of adult T-cell leukemia/lymphoma
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DOI：
10.1182/blood.2021013568
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发表时间：
2022-02-17
期刊：
影响因子：
20.3
通讯作者：
Kataoka, Keisuke
中科院分区：
文献类型：
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作者：
Kogure, Yasunori;Kameda, Takuro;Kataoka, Keisuke
成人T细胞白血病/淋巴瘤（ATL）是一种侵袭性肿瘤，免疫表型类似于调节性T细胞，与人类T细胞白血病病毒1型相关。在这里，我们对150例ATL病例进行了全基因组测序（WGS），以揭示ATL遗传变异的总体情况。我们发现了频繁的（33%）功能丧失改变，优先靶向CIC长亚型，这被以前以外显子组为中心的各种癌症类型的研究所忽视。Cic的长而非短的同种型特异性失活选择性地增加体内CD 4（+）CD 25（+）Foxp 3（+）T细胞。我们还发现了复发性（13%）39-截断的REL，诱导转录上调，并产生功能获得性蛋白。更重要的是，REL截短在弥漫性大B细胞淋巴瘤中也很常见，特别是在生发中心B细胞样亚型中（12%）。在非编码基因组中，我们确定了几个驱动基因的调控元件，特别是剪接位点的经常性突变。此外，我们的特点是不同的突变过程中操作的簇超突变位点内和外的免疫球蛋白/T细胞受体基因，并确定了突变富集在宿主和病毒转录因子的结合位点，这表明他们在ATL的活动。通过结合对编码和非编码突变、结构变异和拷贝数改变的分析，我们发现了56个反复改变的驱动基因，其中包括11个新的驱动基因。最后，ATL病例被分为2个分子组，具有不同的临床和遗传特征的基础上的驱动程序改变的档案。我们的研究结果不仅有助于改善ATL的诊断和治疗策略，而且还提供了对T细胞生物学的见解，并对全基因组癌症驱动因素的发现产生了影响。
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4(+)CD25(+)Foxp3(+) T cells in vivo. We also found recurrent (13%) 39-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.