慢性淋巴细胞白血病的分子图谱及其对预后的影响。
Molecular map of chronic lymphocytic leukemia and its impact on outcome.
机构信息
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Harvard University, Cambridge, MA, USA.
出版信息
Nat Genet. 2022 Nov;54(11):1664-1674. doi: 10.1038/s41588-022-01140-w. Epub 2022 Aug 4.
Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.
近年来，癌症特征的研究不断揭示出明显的异质性，这阻碍了对每种恶性肿瘤进行综合分子和临床图谱的构建。在这里，我们重点关注慢性淋巴细胞白血病（CLL），这是一种具有不同自然史的 B 细胞肿瘤，通常分为两种亚型，其区分标准是免疫球蛋白基因重链可变区（IGHV）中体细胞突变的程度。为了构建“CLL 图谱”，我们整合了 1148 名患者的基因组、转录组和表观基因组数据。我们确定了 202 个 CLL 的候选遗传驱动因素（其中 109 个是新的），并对 IGHV 亚型的特征进行了细化，这揭示了不同的基因组景观和白血病发生轨迹。新的基因表达亚型的发现进一步细分了这种肿瘤，并被证明是独立的预后因素。临床结果与遗传、表观遗传和基因表达特征的组合有关，这进一步推进了我们的预后模型。总的来说，这项工作揭示了对 CLL 致癌和预后的新见解。
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