双倍型 DNMT3A 突变髓样肿瘤的分布情况

IF 29.5 1区 医学 Q1 HEMATOLOGY
Naomi Kawashima, Yasuo Kubota, Carlos Bravo-Perez, Luca Guarnera, Nakisha D. Williams, Arda Durmaz, Michaela Witt, Arooj Ahmed, Carmelo Gurnari, Jaroslaw P. Maciejewski, Valeria Visconte
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引用次数: 0

摘要

DNA 甲基转移酶 3 A 突变(DNMT3AMT)在髓样肿瘤(MN)中很常见,而且大多为杂合突变。然而,也可能出现多个 DNMT3AMT 的病例,但其临床和遗传学特征仍未得到研究。我们回顾性分析了 5603 例连续 MN 中发现的 533 例 DNMT3AMT 病例,其中 8.4% 的病例有多个 DNMT3AMT 基因突变。它们在急性髓性白血病(AML)中最为常见,R882变体占多重命中的13.3%。与单个 DNMT3AMT 患者相比,多个 DNMT3AMT 更有可能与 IDH2(P = 0.005)和 ETV6(P = 0.044)突变同时发生。当多个 DNMT3AMT 的变异等位基因频率(VAF)之和超过 60% 时,我们发现这两个 DNMT3A 变异具有显著的正克隆负荷相关性(P < 0.0001),这表明它们以双等位基因的形式出现。与单拷贝 DNMT3AMT 相比,双拷贝 DNMT3A 失活的急性髓细胞性白血病患者(n = 52)年龄更大(P = 0.029),白细胞(P < 0.0001)和外周血鼓泡计数更高(P = 0.0001),存活率明显更低(2 年存活率为 5.6% 对 47.6%;P = 0.002)。多变量分析发现,双复制DNMT3AMT(HR 2.65;P = 0.001)、男性性别(HR 2.05;P = 0.014)和根据欧洲白血病网2022分类的不良基因改变(HR 1.84;P = 0.028)是影响生存的独立不利因素,而强化化疗(HR 0.47;P = 0.011)对预后有有利影响。对12例双拷贝DNMT3AMT病例的纵向分子分析表明,在9例复发或转化病例(75%)中,此类克隆持续存在或扩大,这表明双拷贝基因突变的早期起源具有很强的致白血病潜能。我们的研究表明,双拷贝 DNMT3AMT 虽然罕见,但确实有可能发生克隆扩增,因此对合成致死策略的适用性提出了质疑。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Landscape of biallelic DNMT3A mutant myeloid neoplasms
DNA methyltransferase 3 A mutations (DNMT3AMT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3AMT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3AMT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3AMT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3AMT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3AMT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3AMT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3AMT. Multivariate analysis identified biallelic DNMT3AMT (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3AMT demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3AMT, while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies.
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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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