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課題背景：大部分急性髓性白血?。ˋML）患者的遺傳致病因素仍然未知。近期華盛頓大學(xué)圣路易斯醫(yī)學(xué)院的一個(gè)研究小組證實(shí)了一個(gè)特異基因的突變可影響急性髓性白血病的治療預(yù)后，該研究報(bào)告在線發(fā)表在2010年11月11日的《新英格蘭醫(yī)學(xué)期刊》（New England Journal of Medicine）上。研究人員最初對一名AML患者和一名正常人同時(shí)進(jìn)行全基因組測序，鑒定到DNA甲基轉(zhuǎn)移酶DNMT3A上有突變，隨后在280名原發(fā)性急性髓性白血患者中，針對DNMT3A的外顯子進(jìn)行測序，結(jié)果發(fā)現(xiàn)在22.1%的AML患者中攜帶有影響DNMT3A翻譯的突變，這些突變包括錯(cuò)義突變、無義突變、移碼突變、剪接位點(diǎn)突變及大片段缺失突變。而上述這些突變高度集中在那些基于細(xì)胞學(xué)檢測歸類于有中度風(fēng)險(xiǎn)的患者中（占33.7%的比例，P<0.001）。 所用關(guān)鍵技術(shù)：全基因組測序，常規(guī)測序，拷貝數(shù)檢測。全基因組DNA測序技術(shù)能夠發(fā)現(xiàn)所有引起癌癥的常見高頻的遺傳改變，在腫瘤基因組學(xué)中，可以進(jìn)行與治療預(yù)后相關(guān)的biomarker的尋找，并為闡明腫瘤的發(fā)生與轉(zhuǎn)移機(jī)制奠定基礎(chǔ)，為可能的藥物開發(fā)提供理論依據(jù)。 課題結(jié)果和討論，意義：在存活的AML患者中，攜帶DNMT3A突變的與不攜帶DNMT3A突變的患者存活時(shí)間分別為12.3個(gè)月和41.1 個(gè)月 (P<0.001)。雖然以前的研究已證實(shí)AML存在有一些候選基因變異，。但在本研究中研究人員發(fā)現(xiàn)：在那些基于細(xì)胞學(xué)檢測歸類于有中度風(fēng)險(xiǎn)的患者或攜帶FLT3（AML候選基因）基因突變的患者中，DNMT3A基因突變與接受常規(guī)化療的不良預(yù)后有關(guān)?，F(xiàn)在醫(yī)生們可通過對患者進(jìn)行這些突變篩查來相應(yīng)調(diào)整他們的治療策略，如果患者有DNMT3A突變，直接進(jìn)行骨髓移植或接受更敏感的化療也許將會是更積極有效的治療方法。該發(fā)現(xiàn)將快速推動(dòng)AML患者個(gè)體化治療，并為治療藥物的開發(fā)提供一個(gè)可能的新的分子靶點(diǎn)。然而本實(shí)驗(yàn)中同樣存在樣本數(shù)量太少的問題，接下去有關(guān)研究者可以進(jìn)一步在更多樣本中，而且最好在不同國家、地區(qū)的樣本中來重復(fù)確認(rèn)這些初步的研究結(jié)果，以期上述實(shí)驗(yàn)結(jié)果在更多、更廣的AML人群中得到驗(yàn)證，為人類攻克腫瘤的事業(yè)加磚添瓦。 參考文獻(xiàn)：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.). |
