The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

IF 3.3 2区医学 Q2 GENETICS & HEREDITY

Human Mutation Pub Date : 2023-05-09 DOI:10.1155/2023/4880113

Grégory Lazarian, Bernard Leroy, Floriane Theves, Myriam Hormi, Rémi Letestu, Virginie Eclache, Giulia Tueur, Adam Ameur, Audrey Bidet, Pascale Cornillet-Lefebvre, Frédéric Davi, Eric Delabesse, Marie-Hélène Estienne, Pascaline Etancelin, Olivier Kosmider, Sophy Laibe, Marc Muller, Nathalie Nadal, Dina Naguib, Cédric Pastoret, Stéphanie Poulain, Pierre Sujobert, Lauren Veronese, Samia Imache, Valérie Lefebvre, Florence Cymbalista, Fanny Baran-Marszak, Thierry Soussi, French Innovative Leukemia Organization (FILO)

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Abstract

TP53 aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal TP53 abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of TP53 variants in CLL, 1,056 TP53 variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 TP53 variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by TP53 to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of TP53 status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple TP53 variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed TP53 mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.

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CLL中TP53突变的广谱:多克隆性和新突变热点的证据

TP53异常是慢性淋巴细胞白血病(CLL)化疗免疫治疗耐药的主要预测因素，在每条治疗线之前对其进行评估是治疗分层的必要条件。获得亚克隆TP53异常是CLL进化的基础。为了更好地表征TP53变异在CLL中的分布、组合和影响，我们分析了法国一项多中心合作研究中从683名患者中收集的1056个TP53变异，并与UMD_CLL进行了比较，UMD_CLL是一个由已发表的文章构建的数据集，共提供了3,808名患者中检测到的5,173个TP53变异。我们的分析证实了几个cll特异性热点突变的存在，包括密码子209的双碱基对缺失和密码子234的错义变异，后者与烷基化处理有关。我们的分析还在内含子6的剪接受体信号中发现了一种新的cll特异性变异，导致使用一个隐剪接位点，类似于TP53产生p53psi，这是一种位于线粒体中的自然截断的p53同种异构体。UMD_CLL的检查和最近发布的CLL患者的几项大规模基因组分析证实，与其他癌症类型相比，这种剪接变体在这种疾病中高度富集。利用tp53特异性单核苷酸多态性，我们也证实了拷贝中性的杂合性缺失在CLL中很常见。这一事件可导致对TP53状态的误解。与其他癌症不同，CLL患者携带多种TP53变异的比例很高。使用硅分析和单分子智能测序，我们证明了在不同等位基因上携带突变的不同亚克隆的共存。总之，我们的研究提供了CLL中详细的TP53突变结构，并为治疗如何塑造CLL患者的遗传景观提供了见解。

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来源期刊

Human Mutation 医学-遗传学

CiteScore

8.40

自引率

5.10%

发文量

190

审稿时长

2 months

期刊介绍： Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.