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伴有 11q23/KMT2A 重排的儿童急性髓系白血病的突变特征和临床结局。

Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements.

机构信息

Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.

出版信息

Cancer Med. 2023 Jan;12(2):1418-1430. doi: 10.1002/cam4.5026. Epub 2022 Jul 14.

DOI:10.1002/cam4.5026
PMID:35833755
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9883550/
Abstract

BACKGROUND

Alterations of 11q23/KMT2A are the most prevalent cytogenetic abnormalities in acute myeloid leukemia (AML) and the prognostic significance of 11q23/KMT2A-rearranged AML based on various translocation partners varies among different studies. However, few studies evaluated the molecular characteristics of 11q23/KMT2A-rearranged pediatric AML. We aim to analyze the mutational landscape of 11q23/KMT2A-rearranged AML and assess their prognostic value in outcomes.

METHODS

The mutational landscape and clinical prognosis of 105 children with 11q23/KMT2A-rearranged AML in comparison with 277 children with non-11q23/KMT2A-rearranged AML were analyzed using publicly accessible next-generation sequencing data from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset.

RESULTS

Pediatric AML patients with 11q23/KMT2A-rearrangements harbored a low number of mutations (Median, 1 mutation/patient, range, 1-22), 58% of which involved in RAS pathway mutations (KRAS, NRAS, and PTPN11) and 10.5% of which comprised of SETD2 mutations. Compared with non-11q23/KMT2A-rearranged AML, the incidence of KRAS (32.4% vs. 10.1%, P〈0.001) and SETD2 (10.5% vs. 1.4%, P=0.001) gene mutations in 11q23/KMT2A-rearranged AML was significantly higher. Both KRAS and SETD2 mutations occurred more often in t(10;11)(p12;q23). KRAS mutations were correlated with worse 5-year event-free survival [EFS] (Plog-rank = 0.001) and 5-year overall survival [OS] (Plog-rank = 0.009) and the presence of SETD2 mutations increases the 5-year relapse rate (PGray = 0.004). Multivariate analyses confirmed KRAS mutations in 11q23/KMT2A-rearranged AML as an independent predictor for poor EFS (hazard ratio [HR] = 2.10, P=0.05) and OS (HR = 2.39, P=0.054).

CONCLUSION

Our findings show that pediatric patients with 11q23/KMT2A rearrangements have characteristic mutation patterns and varying clinical outcomes depending on different translocation partners, which could be utilized to develop more accurate risk stratification and tailored therapies.

摘要

背景

11q23/KMT2A 改变是急性髓系白血病（AML）中最常见的细胞遗传学异常，基于不同的易位伙伴，11q23/KMT2A 重排 AML 的预后意义在不同的研究中有所不同。然而，很少有研究评估 11q23/KMT2A 重排的儿科 AML 的分子特征。我们旨在分析 11q23/KMT2A 重排 AML 的突变景观，并评估其在预后方面的预后价值。

方法

利用 Therapeutically Applicable Research to Generate Effective Treatments（TARGET）数据集的公开可用下一代测序数据，分析 105 例 11q23/KMT2A 重排 AML 患儿与 277 例非 11q23/KMT2A 重排 AML 患儿的突变景观和临床预后。

结果

11q23/KMT2A 重排的儿科 AML 患者突变数量较少（中位数为 1 个突变/患者，范围为 1-22），58%的突变为 RAS 通路突变（KRAS、NRAS 和 PTPN11），10.5%的突变为 SETD2 突变。与非 11q23/KMT2A 重排 AML 相比，11q23/KMT2A 重排 AML 中 KRAS（32.4%比 10.1%，P〈0.001）和 SETD2（10.5%比 1.4%，P=0.001）基因突变的发生率明显更高。KRAS 和 SETD2 突变均发生于 t（10；11）（p12；q23）。KRAS 突变与 5 年无事件生存率（EFS）（Plog-rank = 0.001）和 5 年总生存率（OS）（Plog-rank = 0.009）较差相关，SETD2 突变的存在增加了 5 年复发率（PGray = 0.004）。多变量分析证实，11q23/KMT2A 重排 AML 中的 KRAS 突变是 EFS（危险比[HR] = 2.10，P=0.05）和 OS（HR = 2.39，P=0.054）不良的独立预测因素。

结论

我们的研究结果表明，患有 11q23/KMT2A 重排的儿科患者具有特征性的突变模式，并且根据不同的易位伙伴具有不同的临床结局，这可以用于开发更准确的风险分层和针对性治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/7db535064e44/CAM4-12-1418-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/7f6123ffdc8e/CAM4-12-1418-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/03dca2420a93/CAM4-12-1418-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/7db535064e44/CAM4-12-1418-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/7f6123ffdc8e/CAM4-12-1418-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/ece4a6c1de13/CAM4-12-1418-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/03dca2420a93/CAM4-12-1418-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/59a9b73435be/CAM4-12-1418-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9aa/9883550/7db535064e44/CAM4-12-1418-g002.jpg

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