急性髓细胞白血病的整体遗传特征轮廓预后相关性研究

2025-10-14 999+ 133.5KB 26 页海报

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Prognostic Relevance of Integrated Genetic Profiling in Acute

Myeloid Leukemia

急性髓细胞白血病的整体遗传特征轮廓预后相关性研究

Jay P. Patel, Mithat Gönen, Ph.D., Maria E. Figueroa, M.D., Hugo Fernandez, M.D.,

Zhuoxin Sun, Ph.D., Janis Racevskis, Ph.D., Pieter Van Vlierberghe, Ph.D., Igor

Dolgalev, B.S., Sabrena Thomas, B.S., Olga Aminova, B.S., Kety Huberman, B.S.,

Janice Cheng, B.S., Agnes Viale, Ph.D., Nicholas D. Socci, Ph.D., Adriana Heguy,

Ph.D., Athena Cherry, Ph.D., Gail Vance, M.D., Rodney R. Higgins, Ph.D., Rhett P.

Ketterling, M.D., Robert E. Gallagher, M.D., Mark Litzow, M.D., Marcel R.M. van

den Brink, M.D., Ph.D., Hillard M. Lazarus, M.D., Jacob M. Rowe, M.D., Selina

Luger, M.D., Adolfo Ferrando, M.D., Ph.D., Elisabeth Paietta, Ph.D., Martin S.

Tallman, M.D., Ari Melnick, M.D., Omar Abdel-Wahab, M.D., and Ross L. Levine,

M.D.

Abstract

Background

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to

presentation and clinical outcome. The prognostic value of recently identified somatic

mutations has not been systematically evaluated in a phase 3 trial of treatment for

AML.

急性髓细胞白血病是一种有关表达和临床结果异构性疾病。最近发现的体细胞

突变的预后价值尚用于急性髓细胞白血病治疗的临床三期试验的系统评价。

Methods

We performed a mutational analysis of 18 genes in 398 patients younger than 60 years

of age who had AML and who were randomly assigned to receive induction therapy

with high-dose or standard-dose daunorubicin. We validated our prognostic findings

in an independent set of 104 patients.

我们选择年龄小于 60 岁的 AML398 例随机分配到高剂量组或标准剂量组，接受

柔红霉素的诱导治疗，治疗后对 18 个基因作突变的分析。并另选择 104 例患者

进行验证了预后结果

Results

We identified at least one somatic alteration in 97.3% of the patients. We found that

internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL

(MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced

overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for

ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with

improved over-all survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The

favorable effect of NPM1 mutations was restricted to patients with co-occurring

NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that

improved risk stratification among patients with AML, independently of age, white-

cell count, induction dose, and post-remission therapy, and validated the significance

of these predictors in an independent cohort. High-dose daunorubicin, as compared

with standard-dose daunorubicin, improved the rate of survival among patients with

DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among

patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67).

我们可以确定 97.3%的患者至少有一个细胞发生了改变。在 FLT3 基因中存在串

联重复（FLT3-ITD），在 MLL 基因中存在部分串联重复（MLL-

PTD），ASXL1，PHF6 突变与降低总体生存率相关(P = 0.001 for FLT3-ITD, P

= 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6)；CEBPA

和IDH2 突变与总生存率改善相关(P = 0.05 for CEBPA and P = 0.01 for

IDH2)。NPM1 突变的有利作用仅限于 NPM1 和IDH1 或IDH2 同时发生突变患

者。我们确定的改进 AML 患者危险分层之间遗传因素预测因子，该因子独立

于年龄、白细胞计数、诱导剂量和治疗后缓解治疗，并通过独立的队列验证这

些预测因子的重要性。

Conclusions

We found that DNMT3A and NPM1 mutations and MLL translocations predicted an

improved outcome with high-dose induction chemotherapy in patients with AML.

These findings suggest that mutational profiling could potentially be used for risk

stratification and to inform prognostic and therapeutic decisions regarding patients

with AML. (Funded by the National Cancer Institute and others.)

我们发现 DNMT3A 和NPM1 突变和 MLL 易位预测高剂量诱导化疗的 AML 患

者的转归改善结果。研究结果表明，突变谱可能被用于 AML 患者的危险分层

和预后预测和治疗决策

Previous studies have highlighted the clinical and biologic heterogeneity of acute

myeloid leukemia (AML).1-4。 However, a relatively small number of cytogenetic

and molecular lesions have sufficient relevance to influence clinical practice.5 The

prognostic relevance of cytogenetic abnormalities has led to the wide-spread adoption

of risk stratification, with patients divided into three cytogenetically defined risk

groups with significant differences in over-all survival.6 More recently, FLT3, NPM1,

and CEBPA mutational analysis was shown to improve risk stratification for patients

who do not have karyotypic abnormalities.7 Although progress has been made in

defining prognostic markers for AML, a substantial percentage of patients lack a

specific abnormality of prognostic significance. In addition, there is considerable

heterogeneity in the outcome for individual patients in each risk group.

以前的研究都强调，急性髓细胞白血病的临床和生物学异质性。然而，相对较

少的细胞遗传学和分子病变具有充分的关联性而影响临床实践。细胞遗传异常

的预后相关性促使广泛采用危险因素分层，患者根据细胞遗传学定义的风险分

为三组，其所有生存时间有显著差异。最近，NPM1，FLT3，和 CEBPA 突变分

析显示没有核型畸形患者改善危险分层。虽然在确定的预后标记的 AML 取得

了进展，相当比例的患者缺乏特异性预后差异。此外，各风险组中存在有相当

大的异质性结果。

Recent studies have identified novel recurrent somatic mutations in patients with

AML. These include mutations in TET2,8,9 ASXL1,10 IDH1 or IDH2,11-13

DNMT3A,4,14 and PHF6.15 Retrospective analyses suggest that a subset of these

mutations may have prognostic significance in AML,4,14,16 although these findings

have not been validated with detailed clinical and mutational annotation in large,

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标签： #白血病

摘要：

《急性髓细胞白血病的整体遗传特征轮廓预后相关性研究》摘要研究聚焦急性髓细胞白血病（AML）旨在系统评价近期发现的体细胞突变在AML治疗三期试验中的预后价值。研究选取398例小于60岁的AML患者随机分配至高剂量或标准剂量柔红霉素组接受诱导治疗并对18个基因进行突变分析另选104例患者验证预后结果。研究发现973的患者至少有一个细胞发生改变。FLT3基因串联重复、MLL基因部分串联重复、ASXL1和PHF6突变与降低总体生存率相关；CEBPA和IDH2突变与总生存率改善相关；NPM1突变的有利作用仅限于与IDH1或IDH2同时突变患者。研究还确定了改进AML患者危险分层的遗传因素预测因子且验证了其重要性。此外DNMT3A和NPM1突变和MLL易位可预测高剂量诱导化疗的AML患者转归改善。研究结果表明突变谱可用于AML患者的危险分层、预后预测和治疗决策。

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