课题背景：大部分急性髓性白血病（AML）患者的遗传致病因素仍然未知。近期华盛顿大学圣路易斯医学院的一个研究小组证实了一个特异基因的突变可影响急性髓性白血病的治疗预后，该研究报告在线发表在2010年11月11日的《新英格兰医学期刊》（New England Journal of Medicine）上。研究人员最初对一名AML患者和一名正常人同时进行全基因组测序，鉴定到DNA甲基转移酶DNMT3A上有突变，随后在280名原发性急性髓性白血患者中，针对DNMT3A的外显子进行测序，结果发现在22.1%的AML患者中携带有影响DNMT3A翻译的突变，这些突变包括错义突变、无义突变、移码突变、剪接位点突变及大片段缺失突变。而上述这些突变高度集中在那些基于细胞学检测归类于有中度风险的患者中（占33.7%的比例，P<0.001）。

所用关键技术：全基因组测序，常规测序，拷贝数检测。全基因组DNA测序技术能够发现所有引起癌症的常见高频的遗传改变，在肿瘤基因组学中，可以进行与治疗预后相关的biomarker的寻找，并为阐明肿瘤的发生与转移机制奠定基础，为可能的药物开发提供理论依据。

课题结果和讨论，意义：在存活的AML患者中，携带DNMT3A突变的与不携带DNMT3A突变的患者存活时间分别为12.3个月和41.1 个月 (P<0.001)。虽然以前的研究已证实AML存在有一些候选基因变异，。但在本研究中研究人员发现：在那些基于细胞学检测归类于有中度风险的患者或携带FLT3（AML候选基因）基因突变的患者中，DNMT3A基因突变与接受常规化疗的不良预后有关。现在医生们可通过对患者进行这些突变筛查来相应调整他们的治疗策略，如果患者有DNMT3A突变，直接进行骨髓移植或接受更敏感的化疗也许将会是更积极有效的治疗方法。该发现将快速推动AML患者个体化治疗，并为治疗药物的开发提供一个可能的新的分子靶点。然而本实验中同样存在样本数量太少的问题，接下去有关研究者可以进一步在更多样本中，而且最好在不同国家、地区的样本中来重复确认这些初步的研究结果，以期上述实验结果在更多、更广的AML人群中得到验证，为人类攻克肿瘤的事业加砖添瓦。

参考文献：Ley TJ, Ding L, Walter MJ, etal. DNMT3A mutations in acute myeloid leukemia. NEJM. 2010; 363(25): 2460-2461. Abstract

BACKGROUND: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.

METHODS: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations.

RESULTS: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. CONCLUSIONS: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.).