NEW YORK – Cancer may stem from transient epigenetic changes, even in the absence of related genetic alterations, according to a new study in fruit flies published in Nature on Wednesday.

纽约——周三发表在《自然》杂志上的一项关于果蝇的新研究表明，即使没有相关的基因改变，癌症也可能源于短暂的表观遗传变化。

'Cancer is generally believed to arise as a consequence of the accumulation of somatic mutations, frequently involving multiple mutational hits,' co-senior and co-corresponding author Giacomo Cavalli, a researcher affiliated with the University of Montpellier and CNRS in France, said in an email, adding that 'some human cancers have a low or undetectable driver mutation burden.'.

法国蒙彼利埃大学（University of Montpellier）和北卡罗来纳州立大学（CNRS）附属研究人员、联合通讯作者贾科莫·卡瓦利（Giacomo Cavalli）在一封电子邮件中说：“人们普遍认为，癌症是由于体细胞突变的积累而产生的，通常涉及多次突变。”。

In addition, he explained, prior studies have hinted that epigenetic shifts can occur in the absence of new genetic alterations in metastatic tumors that develop from primary tumors containing certain driver mutations.

此外，他解释说，先前的研究已经暗示，在由含有某些驱动突变的原发性肿瘤发展而来的转移性肿瘤中，如果没有新的遗传改变，则可能发生表观遗传转变。

To explore epigenetic effects on cancer risk, Cavalli and colleagues at the University of Montpellier; the Vienna BioCenter; the University of California, Los Angeles; and other international centers performed RNA interference experiments on developing Drosophila larvae, focusing on a conserved gene silencing complex known as Polycomb..

为了探索表观遗传对癌症风险的影响，卡瓦利和蒙彼利埃大学的同事们；维也纳生物中心；加利福尼亚大学洛杉矶分校；和其他国际中心对发育中的果蝇幼虫进行了RNA干扰实验，重点是一种保守的基因沉默复合物，称为Polycomb。。

'Over the last decade, substantial evidence has been provided showing that many epigenetic components … are perturbed in many types of cancers,' Cavalli said. '[W]hat was not known is whether cancer can be induced by a pure epigenetic perturbation without accompanying driver DNA mutations and how that would work.'.

卡瓦利说：“过去十年来，大量证据表明，许多表观遗传成分……在许多类型的癌症中都受到干扰。”[W] 目前尚不清楚的是，癌症是否可以由纯粹的表观遗传扰动诱导，而不会伴随驱动DNA突变，以及这将如何工作。

Indeed, after using thermosensitive RNAi experiments to reversibly dial down the PH subunit of the Polycomb Repressive Complex 1 (PRC1) in eye imaginal disc tissue, the team saw tumors form by the third larval stage in the developing fruit flies.

事实上，在使用热敏RNAi实验可逆地降低眼假想盘组织中多梳抑制复合物1（PRC1）的PH亚基后，研究小组看到了发育中的果蝇在第三个幼虫阶段形成的肿瘤。

That tumor formation did not appear to be explained by the presence of new genetic mutations, based on whole-genome sequencing analyses of tumor and normal tissue samples from the larvae with or without Polycomb knockdown.

基于对有或没有Polycomb敲除的幼虫的肿瘤和正常组织样品的全基因组测序分析，似乎没有新基因突变的存在来解释肿瘤的形成。

'No genes contained deleterious [single nucleotide variants or small insertions or deletions] in all tumor samples, and similar results were found when considering structural variants or copy number variations,' the authors reported, adding that these and other results 'argue strongly against the presence of recurrent driver mutations in these tumors.'.

“在所有肿瘤样本中，没有基因含有有害的[单核苷酸变异或小的插入或缺失]，当考虑结构变异或拷贝数变异时，发现了类似的结果，”作者报道，并补充说，这些和其他结果“强烈反对这些肿瘤中复发性驱动突变的存在。”。

On the other hand, when the team used approaches such as RNA sequencing, chromatin immunoprecipitation sequencing, and ATAC-seq to track the transcriptomic and chromatin accessibility consequences of the transient PRC1 knockdown, it found reversible expression changes as well as expression shifts that persisted after activity of the Polycomb complex was restored..

另一方面，当该团队使用RNA测序，染色质免疫沉淀测序和ATAC-seq等方法来追踪瞬时PRC1敲低的转录组学和染色质可及性后果时，它发现可逆的表达变化以及Polycomb复合物活性恢复后持续存在的表达变化。。

'[W]e show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila,' the authors reported.

作者报道说：“我们发现，Polycomb组蛋白介导的转录沉默的瞬时扰动足以诱导果蝇不可逆地转变为癌细胞的命运。”。

In particular, the researchers suggested that the transient Polycomb silencing led to irreversible regulatory changes to the JAK-STAT signaling pathway and to the fruit fly version of a gene known to be an oncogene in mammals, leading to derepression of these genes in the tumors that they dubbed 'epigenetically initiated cancers.'.

特别是，研究人员认为，短暂的Polycomb沉默导致JAK-STAT信号通路和果蝇版本的已知哺乳动物致癌基因发生不可逆的调节变化，导致这些基因在肿瘤中的去阻遏，他们称之为“表观遗传引发的癌症”。

'These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations,' the authors wrote, 'suggesting that tumors can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.'

“这些数据表明，在没有驱动突变的情况下，Polycomb蛋白的可逆消耗可以诱发癌症，”作者写道，“这表明肿瘤可以通过表观遗传失调而出现，从而导致细胞命运改变的遗传。”

Based on their subsequent analysis of published data on solid cancer and multiple myeloma cases, the investigators suggested that epigenetic changes may have similar consequences in human cancers, since cases marked by lower-than-usual expression of the PRC1 Polycomb subunit tended to show poorer-than-usual overall survival outcomes..

根据他们随后对已发表的实体癌和多发性骨髓瘤病例数据的分析，研究人员认为表观遗传变化可能在人类癌症中产生类似的后果，因为PRC1多梳亚基表达低于正常水平的病例往往表现出比通常更差的总体生存结果。。

Cavalli suggested that such findings may ultimately improve investigators' understanding of cancer development. They could also potentially inform treatment strategies used to tackle forms of cancer that are marked by low mutation levels compared to treatments for mutation-rich tumors.

卡瓦利认为，这些发现可能最终会提高研究人员对癌症发展的理解。与突变丰富的肿瘤治疗相比，它们还可能为治疗以低突变水平为特征的癌症提供潜在的治疗策略。

In a related commentary in Nature, University of Freiburg researcher Anne-Kathrin Classen, who was not involved in the study, noted that the results point to the need for profiling both genetic and epigenetic features in tumors to better understand and treat cancer.

在《自然》杂志的一篇相关评论中，弗莱堡大学的研究人员安妮·凯瑟琳·克拉森（AnneKathrinClassen）没有参与这项研究，她指出，研究结果表明需要分析肿瘤的遗传和表观遗传特征，以更好地理解和治疗癌症。

'In people, temporary epigenetic changes might arise from environmental influences that are specific to an individual's life history, such as certain diets or medications, or exposure to chemical agents,' Classen wrote. 'Consequently, approaches to the experimental analyses of tumors need to take these transient events into account and consider their long-term consequences.'.

Classen写道：“在人类中，暂时的表观遗传变化可能来自特定于个体生活史的环境影响，例如某些饮食或药物，或暴露于化学制剂。”因此，肿瘤实验分析的方法需要考虑这些短暂事件并考虑其长期后果。”。