BACKTRACKING TRANSLOCATIONS IN CHILDHOOD LEUKEMIA

描述（由申请人提供）：白血病是儿童中最常见的癌症，是发病、压力和长期后遗症的重要原因。尽管在治疗方面取得了进展，可以治愈大多数白血病，但我们仍然对这种疾病的原因知之甚少，阻碍了任何预防的尝试。我们的重点是在分子上详细描述白血病中发生的染色体和突变变化，并使用这些遗传畸变来开发研究这些事件的时间和因果关系的工具。目前，我们已经集中在易位，发现大多数，但不是所有的易位亚型有一个在子宫内的起源。最常见的儿童易位，t（12;21）TEL-AML 1，发生在25%的儿童急性淋巴细胞白血病中，通常（如果不总是）发生在出生前的儿童中，这些儿童后来感染了这种遗传畸变的白血病。我们现在建议描述TEL-AMLI+白血病中的继发性遗传事件，首先关注12 p缺失，这是TEL-AMLI+白血病中常见的（约75%）事件。我们将使用阵列比较基因组杂交（阵列CGH）来定义12 p染色体缺失的确切断点，允许在基因组核苷酸水平克隆它们。接下来，我们将使用克隆的融合连接作为探针，通过在来自我们也测序和“回溯”基因组TEL-AML 1易位序列的同一儿童的新生儿足跟-针刺古特里卡上搜索该遗传标记的存在，“回溯”白血病至出生。第三，我们将使用12 p缺失沿着TEL-AML 1易位来追踪治疗后儿童中白血病克隆的命运，从而完成这些基因组融合的“自然史”的故事并确定新标记的临床效用。最后，我们将评估在阵列CGH实验中被指示为等位基因丢失的假定肿瘤抑制等位基因的存在。初步结果表明，在一些患者中，12 p上存在一个以上的不同缺失，这表明了这种分析的复杂性和发现潜力。我们的结果将为北方加州儿童白血病研究提供信息和指导，这是一个流行病学项目，我们所有的样本都来自该项目。我们最终将致力于阐明一种可能可以预防的癌症的起源和原因。

DESCRIPTION (provided by applicant): Leukemia is the most common cancer among children and a significant cause of morbidity, stress, and long-term sequelae. Despite advances in treatment that permit a cure in the majority of leukemias, we still know very little about the causes of the disease, thwarting any attempt at prevention. Our focus is to describe in molecular detail the chromosomal and mutational changes that occur in leukemias, and use these genetic aberrations to develop tools to study the timing and causality of these events. Hitherto we have focused on translocations, finding that most but not all translocation subtypes have an in utero origin. The most common childhood translocation, t(12;21) TEL-AML1, occurs in 25% of childhood acute lymphocytic leukemia and usually, if not always, occurs before birth in children who later contract leukemia with this genetic aberration. We now propose to describe the secondary genetic events in TEL-AMLI+ leukemia, focusing first on the 12p deletion, which is a common (~75%) event in TEL-AMLI+ leukemia. We will use array-Comparative Genomic Hybridization (array-CGH) to define the exact breakpoints of 12p chromosomal deletions, allowing their cloning at the genomic nucleotide level. Next, we will use the cloned fusion junction as a probe to "backtrack" leukemia to birth, by searching for the presence of this genetic marker on neonatal heel-prick Guthrie cards from the same children that we have also sequenced and "backtracked" the genomic TEL-AML 1 translocation sequence. Thirdly, we will use 12p deletions along with TEL-AML 1 translocations to track the fate of the leukemia clone in children after therapy, thereby completing the story of the "natural history" of these genomic fusions and determining clinical utility of the novel markers. Lastly, we will assess the presence of putative tumor suppressor allele(s) that are indicated as allelic loss in array-CGH experiments. Preliminary results suggest the presence of more than one distinct deletion on 12p in some patients, demonstrating the complexity and discovery potential of this analysis. Our results will inform and guide the Northern California Childhood Leukemia Study, an epidemiological project from which all of our samples are derived. We are ultimately working to elucidate the origin and causes of a cancer that might be preventable.