有别于成年人!两篇Nature重磅揭示儿童癌症不同的突变特征
2018/03/03
2月28日,《Nature》期刊“背靠背”发表了两篇针对儿童患者进行“泛癌分析”的文章。科学家们第一次梳理了超1700个肿瘤组织的基因组数据,共涉及超20种不同类型的儿童癌症,从中发现儿童癌症与成人癌症在基因突变上有很大的不同,为儿童癌症精准医疗提供了新线索。


图片来源:Illustration by Paddy Mills

“这些数据提醒我们,儿童患者并不是成年患者的‘缩小版’,并不能直接‘套用’成年人的治疗方案。它强调了为儿童癌症患者开发精准治疗药物的必要性。”项目负责人、St. Jude计算生物学主任Jinghui Zhang教授表示道。她带领团队分析了1699名儿童患者(涉及6种癌症类型)的基因组数据。

另一篇文章由来自于德国癌症研究中心的科学家们完成,他们针对24种癌症,比对了961名儿童癌症患者的全基因组、外显子基因组数据。


Jinghui Zhang教授(前排)与两名共同一作Xiaotu Ma和Yu Liu博士(后排)(图片来源:Peter Barta / St. Jude Children's Research Hospital)

儿童癌症现状

某种程度上,研究儿童癌症比成人癌症更容易。这是因为儿童所累积的突变相对较少,从而便于区分“驱动”癌变的突变基因。

但是,儿童癌症数量相对较少,临床试验中注册的患者数量更少,关联肿瘤的基因组信息有限,所以制药公司并不乐意进军这一相对较小的市场。

有别于成人癌症


另一篇由德国癌症研究中心的科学家们发表的文章(doi:10.1038/nature25480)

研究团队采用了了3种完全不同的下一代测序方法,分析了仅存在于癌细胞中的基因突变以及突变对于肿瘤、正常组织的影响。这一方法被称为“泛癌分析”(pan-cancer analysis)

他们发现了超140个可能与癌症发生有关联的基因。但是,只有45%与成人癌症的驱动基因重叠。这意味着,儿童癌症和成人癌症往往关联着不同的基因突变。研究人员认为,一半的突变基因有望成为有用的治疗靶点。

特殊的突变特征


Jinghui Zhang团队的文章(doi:10.1038/nature25795)

Jinghui Zhang团队共分析了6种癌症,包括急性淋巴细胞白血病(ALL,B细胞和T细胞系)、急性髓系白血病(AML)、骨肉瘤(osteosarcoma)、肾母细胞瘤(Wilms tumor)和神经母细胞瘤(neuroblastoma)。

不同于成年人的泛癌分析(主要关注编码序列),此次研究团队重点分析了儿童患者的DNA拷贝数、染色体重排变异。同时,转录组、突变体与野生型等位基因的定量和定性表达也第一次被综合分析。

结果显示,在689名B细胞系急性淋巴细胞白血病患者中,有8名患者携带意想不到的突变特征——他们的DNA突变类型与紫外线照射引发的突变(之前只存在于皮肤癌中)一致。“这一发现表明,暴露于紫外线下可能是一种之前未曾重视的致癌因素,它会增加儿童发生白血病的风险。” 加州大学圣地亚哥分校的Ludmil Alexandrov博士表示道。

另外,62%的致癌突变是DNA拷贝数、结构异常,远高于传统认知的DNA点突变。“拷贝数异常会导致特定基因增加或者减少,而结构异常会引发基因重排。这些结果意味着,未来对儿童患者的精准分析需要考虑这两个因素。” Jinghui Zhang强调道。


儿童癌症与成人癌症的不同之处,包括基因突变率、基因驱动、特异性。(图片来源:Nature)

下一步目标

然而,从基因突变到开发出有效药物,将是一个漫长过程。

来自于Dana-Farber癌症研究所的儿科肿瘤学家Katherine Janeway认为,因为不知道到底有多少分子靶标与儿童癌症有关。但是,其同事Scott Armstrong教授认为,基于基因组学构建数据库是一个良好开端。

事实上,很多实验室试图解析突变引发儿童癌症的细节,例如Broad研究所启动了一个研究项目,利用基因编辑工具研究儿童癌症细胞中突变基因的功能。

现在,这两项重磅研究让我们对于儿童癌症的生物学原因有了进一步的了解,从而为更个性化的诊疗提供了新的方向和依据。

参考资料:

Genome studies unlock childhood-cancer clues

Genomic analysis underscores need for precision therapies that target pediatric cancer

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