在一个单一的核酸碱基的变化，推动儿童癌症

儿科肿瘤学研究人员发现了一个DNA碱基的重要变化，诱发儿童的儿童神经母细胞癌的侵袭性，使疾病进展一旦肿瘤形成。

在变化LMO1基因的结果在一个“超级增强，”驾驶异常增加的生物活性的基因，导致肿瘤的形成和发展。虽然这一发现并不能立即治疗神经母细胞瘤的高危亚型，更大的理解这些精确的分子事件可能会产生新的治疗方法。

John M。马里斯，MD “一般的癌症和神经母细胞瘤，特别是具有复杂的起源，”资深作者John M。马里斯，MD，在费城儿童医院的儿科肿瘤学家（CHOP）。“发现癌症的致病基因变异是不常见的，尤其是在一个单碱基的DNA序列如本内。”DNA的单个碱基的改变称为单核苷酸多态性SNP，或。

这项研究今天在线发表在自然。

A cancer of the peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen, neuroblastoma is the most common cancer in infants。 It accounts for a disproportionate share of cancer deaths in children。

Derek A。 Oldridge, MD - PhD candidate Maris and colleagues, including co-first authors Derek A。 Oldridge, an MD-PhD candidate, and Dr。 Andrew Wood, an assistant professor at the University of Auckland in New Zealand, built on a 2011 genome-wide association study published in 自然 by Maris’s team。 That research showed that common SNPs within the LMO1 gene drive neuroblastoma susceptibility and progression by abnormally altering gene transcription, part of the process by which DNA-encoded information carries out biological functions。 The new study sought to identify the precise variant in the DNA and to learn the molecular mechanisms set in motion by that change。

通过映射如何与控制转录的调控蛋白相互作用，研究者们把这个基因缩小到一个单一的碱基，鸟嘌呤，推动超增强活性的位置，提高LMO1 gene expression and causing tumors to arise and grow out of control。

The researchers also found that another genetic change has a beneficial effect: If the DNA base at the specified location is a different letter of the genetic alphabet, thymine instead of guanine, it protects against neuroblastoma。 Gene studies in human populations suggest that this protective gene variant evolved after human ancestors migrated out of Africa, hundreds of thousands of years ago。

Over the years, researchers at CHOP have discovered a variety of genes contributing to neuroblastoma, and continue to pursue innovative therapies for high-risk, aggressive subtypes of the complex disease。

现有的药物是已知的，以抑制特定的蛋白质，功能异常LMO1-driven neuroblastoma。 However, adds Maris, other components on this biological pathway may offer attractive treatment targets: “Drugs that inhibit other parts of the gene transcription machinery may offer potential novel treatments for this aggressive subset of neuroblastoma。” Further research at CHOP will pursue that strategy。

Oldridge’s research on the super-enhancer was recognized last month by the International Society of Paediatric Oncology, which presented him with 30th annual Schweisguth Prize, awarded to the best scientific article by a trainee in pediatric oncology。

In addition to his CHOP position, Maris is on the faculty of the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Family Cancer Research Institute。

Funds from the National Institutes of Health (grants CA124709, CA180692, CA151869, MD004418, CA178189, HG000046 and CA109901) supported this research。 Other support came from the Press On Foundation, Andrew’s Army Foundation, Alex’s Lemonade Stand Foundation and the Brooke Mulford Foundation, among others。

“神经母细胞瘤的遗传易感性LMO1超级增强多态性自然, published online Nov。 11, 2015。 http://doi。org/10。1038/nature15540

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