对 3760 例血液系统恶性肿瘤的分析揭示了罕见的驱动基因转录组畸变。

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Xueqi Cao, Sandra Huber, Ata Jadid Ahari, Franziska R Traube, Marc Seifert, Christopher C Oakes, Polina Secheyko, Sergey Vilov, Ines F Scheller, Nils Wagner, Vicente A Yépez, Piers Blombery, Torsten Haferlach, Matthias Heinig, Leonhard Wachutka, Stephan Hutter, Julien Gagneur
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引用次数: 0

摘要

背景:罕见的致癌驱动基因事件,尤其是影响驱动基因表达或剪接的事件,被怀疑是导致血液系统恶性肿瘤巨大异质性的主要原因。然而,对它们的鉴定仍具有挑战性:为了解决这个问题,我们建立了迄今为止最大的血液恶性肿瘤全基因组测序和总 RNA 测序匹配数据集,这些数据集来自 3760 例血液恶性肿瘤患者,涵盖 24 个疾病实体。利用数据集的规模优势,我们重点发现了罕见的调控畸变。因此,我们利用工作流 DROP(Detection of RNA Outliers Pipeline,RNA异常检测管道)的扩展功能和 AbSplice(一种可识别导致剪接异常的遗传变异的变异效应预测器)来调用表达和剪接异常值。接下来,我们训练了一个机器学习模型来整合这些结果,以优先选择新的候选疾病特异性驱动基因:我们发现每个样本中位数有 7 个表达异常基因、2 个剪接异常基因和 2 个罕见剪接影响变体。每个类别都显示出对已经表征清楚的驱动基因的明显富集,在五个以上样本中被调用的基因的几率比超过三。在保留的数据中,我们的整合建模明显优于仅基于基因组数据的建模,并揭示了有希望的新型候选驱动基因。值得注意的是,我们发现低密度脂蛋白受体 LRP1B 转录本的截短形式在大约一半的毛细胞白血病变异型(HCL-V)样本中异常过表达,在与之密切相关的 B 细胞肿瘤中也有少量过表达。这一观察结果在一个独立的队列中得到了证实,表明LRP1B是HCL-V亚类的一个新标记物,而且LRP1B在这些罕见实体中的功能作用尚未得到报道:总之,我们对24种血液系统恶性肿瘤实体的表达和剪接异常值的普查以及配套的计算工作流程构成了独特的资源,可加深我们对血液系统癌症罕见致癌事件的了解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes.

Background: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging.

Methods: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes.

Results: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities.

Conclusions: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.

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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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