科学家发现儿童癌症与基因改变有关

一项新研究发现了一组可能与儿童癌症发展相关的基因变异。根据研究结果，影响大片段DNA的基因组变异（称为结构变异）估计导致1%至6%的儿童实体瘤。

结构变异是指在细胞分裂过程中，基因组中大量片段被删除、添加、复制、翻转或移动时发生的变异。研究人员重点研究了生殖细胞系结构变异，即那些在出生时就存在且通常由父母遗传的变异。

为了开展这项研究，研究小组分析了1700多名患有神经母细胞瘤、尤文氏肉瘤或骨肉瘤的儿童的基因组。他们还分析了这些儿童父母以及未患癌症的无亲缘关系成年人的基因组，以进行比较。  

患有癌症的儿童具有更多预测会改变基因功能的结构变异退出免责声明他们发现，与未患癌症的成年人相比，男孩更容易出现涉及大片段DNA的结构变异。而且男孩出现这种变异的可能性远远高于女孩。

这项由 NCI 资助的研究结果于 1 月 3 日发表在《科学》杂志上。

当整个染色体（黄色和紫色）或大块染色体（紫色/粉色）在细胞分裂过程中被删除、复制或插入时，就会发生结构变异。

图片来源：Nadia Jaber 与 Biorender.com 合作创作

“从研究的角度来看，这项研究就像在地上插了一面旗帜，”该研究的联合负责人、丹娜—法伯癌症研究所的计算生物学家瑞安·柯林斯博士说道。“它表明，这是一整类基因变异……与个体在生命早期患癌症的风险有关，至少在我们研究的三种疾病中是如此，”柯林斯博士说。

该研究的另一位共同负责人、丹娜—法伯癌症研究所儿科肿瘤学家 Riaz Gillani 医学博士表示，这些发现将帮助研究人员更好地“了解导致这些疾病的最早生物学机制”。

吉拉尼博士继续说道，随着这种理解的加深，科学家们有望找到精准靶向该生物学机制的治疗方法。他补充说，这种靶向治疗将比目前用于治疗大多数儿童实体瘤的化疗和放疗等“强效疗法”具有诸多优势。

儿童癌症的遗传原因

癌症是由DNA 损伤引起的，它会改变细胞的功能，特别是细胞的生长和分裂方式。

对于成年人来说，人们普遍认为癌症需要几十年的时间才能发展，因为DNA损伤会随着时间的推移而积累，这主要是由于接触致癌物和细胞分裂时发生的自然错误造成的。

但对于在一岁生日之前就可能患上癌症的儿童来说，情况则完全不同。儿童的寿命还不够长，无法积累大量由致癌物和自然DNA错误造成的DNA损伤，因此许多专家怀疑，儿童癌症主要是由遗传基因改变引起的。

CAR-T细胞疗法在治疗儿童致命脑癌方面显示出前景

免疫疗法使 11 名弥漫性中线胶质瘤患者中的 7 名的肿瘤缩小。

目前已确定8% 至 10% 的儿童癌症是由遗传基因改变引起的退出免责声明，与成人肿瘤中观察到的相似。

但NCI数据共享办公室主任Jaime Guidry Auvil博士表示，这一估计几乎完全来自对“基因组中微小变化和变异”的研究，例如DNA密码中的单字母转换。Guidry Auvil博士曾领导过多个儿童癌症基因组项目，但并未参与这项新研究。

柯林斯博士解释说， 由于传统DNA 测序技术的限制，结构变异会影响 50 到 100 万个 DNA 字母，因此研究起来更加困难。

他说：“直到最近我们才开始真正了解如何检测人类基因组中这些类型的种系重排。”

结构变异破坏关键基因

为了确定可能增加儿童癌症风险的种系结构变异，研究小组比较了约 1,700 名癌症儿童、超过 900 名儿童父母以及超过 6,000 名无癌症的无关成年人的 DNA。

柯林斯博士解释说，普通人有数千种结构变异，研究人员发现，研究中的每个人体内都有超过 5,000 种种系结构变异。

然而，与父母和无亲缘关系的成年人相比，这些儿童平均多出6到10个预测会改变基因功能的结构变异。在许多情况下，结构变异会切断相当大一部分基因。

只有一小部分变异会影响已知的癌症基因或导致遗传性癌症的基因。例如，在患有尤文氏肉瘤和神经母细胞瘤的儿童中，一小部分结构变异抑制了已知癌症基因（有助于修复断裂的DNA）的活性。

其他结构变异会影响对癌症起源器官或组织发育至关重要的基因。例如，神经母细胞瘤起源于神经细胞，神经母细胞瘤患儿的几个对神经细胞发育至关重要的基因受到了结构变异的影响。

吉德里·奥维尔博士表示，这些发现凸显了大规模研究结构变异的重要性。她补充道：“令人高兴的是，我们拥有来自许多儿童癌症项目的全基因组测序数据，能够进行这些分析”，包括TARGET项目、加布里埃拉·米勒儿童优先儿科研究项目和儿童癌症数据倡议项目。

患癌症的男孩有更多较大的结构变异

研究人员还重点研究了大型结构变异——那些涉及超过一百万个DNA碱基的变异。大型结构变异会增加多种发育障碍的风险，因此研究小组推断，它们也可能与儿童癌症有关。

正如他们所怀疑的那样，儿童比成年人更容易出现较大的结构变异。

但他们惊讶地发现，这种差异完全是由患癌症的男孩中结构变异的高频率造成的，他们比没有患癌症的男性更有可能出现较大的结构变异。

同样，这些变异中很少有影响已知的癌症基因。相反，它们似乎随机分散在整个基因组中。

柯林斯博士说，这一发现既令人困惑又令人着迷，因为它几乎可以肯定“可能存在我们尚未发现的儿童癌症特异性风险基因”。

“我们必须比传统的已知癌症基因研究更深入，特别是针对这些出现在幼儿身上的肿瘤，”吉德里·奥维尔博士表示同意。

“我们必须以更加开放的心态看待所有数据，”她补充道。

总体而言，研究人员估计，结构变异与1%至6%的神经母细胞瘤、尤文氏肉瘤和骨肉瘤的发生发展有关。研究团队指出，这是一个粗略的估计，由于研究中的儿童数量相对较少，并且由于技术限制而排除了某些类型的结构变异。

儿童癌症没有单一病因

种系遗传变异是指出生时存在于体内每个细胞中的变异。研究人员发现，在这项研究中，癌症患儿DNA中几乎所有的种系结构变异都遗传自父母。

但由于这些孩子的父母没有患癌症，这一发现表明可能还有其他因素在起作用，柯林斯博士解释说。

吉拉尼博士说，人们倾向于思考癌症的“病因和基因”，但癌症很少是由单一原因造成的。

柯林斯博士补充道：“显而易见的下一步是对这些孩子基因组中的所有信息进行整体综合的审视，这不仅包括结构变异，还包括微小突变和其他基因改变。” 他说：“后续研究正在进行中。”

吉德里·奥维尔博士对此表示同意，他表示，“如果我们不尽可能多地收集有关这些小身体内发生的事情的信息，并开始综合研究所有这些发现，包括儿童发育过程中“这些[遗传]事件何时、何地和如何发生”，那么我认为我们对癌症患者的伤害是巨大的。”

理解和针对基因组不稳定性

荷兰马克西玛公主儿科肿瘤中心的 Jayne Hehir-Kwa 博士和西班牙国家癌症研究中心的 Geoff Macintyre 博士在随附的观点中写道，研究结果暗示患有神经母细胞瘤、尤文氏肉瘤和骨肉瘤的儿童可能容易获得过多的遗传错误，这种现象称为基因组不稳定性。

就像地基不牢固的房子一样，基因组不稳定的细胞更容易积累 DNA 变化，例如结构变异。

Hehir-Kwa 博士和 Macintyre 博士补充道，在儿童生长突增期，细胞会快速生长和分裂。他们继续说道，如果儿童的细胞存在基因组不稳定性，这些生长突增可能会为获得大量新的结构变异打开大门。这将使这些儿童患癌症的风险更大。

先前对儿童癌症的研究发现，通常修复受损 DNA 的基因存在微小突变，这也提供了基因组不稳定性可能发挥作用的证据。

Hehir-Kwa 博士和 Macintyre 博士指出，儿童癌症或许可以通过现有的靶向基因组不稳定性药物进行治疗。他们解释说，某些药物，例如 PARP 抑制剂和铂类化疗，对已经存在大量受损 DNA 的癌症更有效。

柯林斯博士和吉拉尼博士表示，总体而言，研究结果指出了一类基因变化，这些变化不仅会导致某些儿童癌症，而且在未来可能成为治疗目标。

来自：https://www.cancer.gov/news-events/cancer-currents-blog/2025/structural-variants-cancer-in-children

Scientists Find Genetic Changes Linked to Cancer in Children

A new study has identified a group of genetic changes that are likely involved in the development of cancer in children. According to the findings, genomic changes affecting large pieces of DNA, called structural variants, contribute to an estimated 1% to 6% of pediatric solid tumors.

Structural variants occur when large chunks of the genome get deleted, added, duplicated, flipped around, or moved during cell division. The researchers focused on germline structural variants, meaning those that are present at birth and typically inherited from a parent.

To conduct the study, the team analyzed the genomes of more than 1,700 children with neuroblastoma, Ewing sarcoma, or osteosarcoma. They also looked at the genomes of the children’s parents and of unrelated adults without cancer, for comparison.  

The children with cancer had more structural variants that were predicted to change the function of a geneExit Disclaimer than the adults without cancer, they found. And boys were much more likely than girls to have structural variants that involved very large pieces of DNA.

Findings from the NCI-funded study were published January 3 in Science.

“From a research perspective, this [study] is really like planting [a] flag in the ground,” said the study’s co-leader, Ryan Collins, Ph.D., a computational biologist at Dana-Farber Cancer Institute. It “shows that this is a whole class of genetic variation that … plays a role in an individual's risk for getting cancer early in life, at least in the three diseases that we studied,” Dr. Collins said.

The findings will help researchers better “understand the earliest biology that leads to these diseases,” said the study’s other co-leader, Riaz Gillani, M.D., a pediatric oncologist at Dana-Farber Cancer Institute.

And with that better understanding, hopefully scientists will find treatments that precisely target that biology, Dr. Gillani continued. Such targeted treatments would have several advantages over the current “sledgehammer approach” of chemotherapy and radiation used to treat most children with solid tumors, he added.

Genetic causes of pediatric cancer

Cancer is caused by damage to DNA that alters how cells function, especially how they grow and divide.

For adults, it’s generally thought that cancer takes decades to develop as DNA damage builds up over time, mostly from exposure to carcinogens and natural errors that occur when cells divide.

But for children, who can develop cancer before their first birthday, it’s an entirely different scenario. Children haven’t lived long enough to accumulate lots of DNA damage from carcinogens and natural DNA errors, so many experts suspect that pediatric cancers are mostly caused by inherited genetic changes.

Inherited genetic changes are currently pinpointed as the cause of 8% to 10% of childhood cancersExit Disclaimer, similar to that observed in adult tumors.

But that estimate comes almost exclusively from studies of “small shifts and variations in the genome,” such as single-letter switches in the DNA code, said Jaime Guidry Auvil, Ph.D., director of NCI’s Office of Data Sharing. Dr. Guidry Auvil has led several childhood cancer genome projects but was not involved in the new study.

Structural variants, which affect 50 to upwards of a million DNA letters, have been harder to study due to technical limitations of traditional DNA sequencing technologies, Dr. Collins explained.

“Only recently have we started to really get a handle on how to detect these types of germline rearrangements in the human genome,” he said.

Structural variants disrupt key genes

To identify germline structural variants that may raise the risk of pediatric cancer, the team compared the DNA of around 1,700 children with cancer, more than 900 parents of those children, and over 6,000 unrelated adults without cancer.

The average person has thousands of structural variants, Dr. Collins explained, and the researchers found more than 5,000 germline structural variants in every individual in the study.

But, compared with their parents and unrelated adults, the children had an average of 6 to 10 more structural variants that were predicted to change the function of a gene. In many cases, the structural variant lopped off a sizable chunk of a gene.

Only a small percentage of the variants affected known cancer genes or genes that cause hereditary cancers. For instance, a small group of structural variants among the children with Ewing sarcoma and neuroblastoma quashed the activity of known cancer genes that help repair broken DNA.

Other structural variants affected genes that are critical for the development of the organ or tissue where the cancer started. Neuroblastoma starts in nerve cells, for example, and several genes that are important for nerve cell development were affected by structural changes in children with neuroblastoma.

These findings highlight the importance of looking at structural variants on a large scale, Dr. Guidry Auvil said. “Happily, we have whole genome sequencing data from many childhood cancer projects to be able to do those analyses” including TARGET, the Gabriella Miller Kids First Pediatric Research Program, and the Childhood Cancer Data Initiative, she added.

Boys with cancer have more large structural variants

The researchers also focused in on large structural variants—those involving more than a million DNA letters. Large structural variants raise the risk of several developmental disorders, so the team reasoned that they may also have a role in pediatric cancer.

As they suspected, the children were more likely than the adults to have a large structural variant.

But they were surprised to find that this difference was entirely driven by the high frequency of structural variants in boys with cancer, who were much more likely to have large structural variants than the men without cancer.

Again, very few of those variants affected known cancer genes. Instead, they appeared to be randomly scattered throughout the genome.

That finding is both perplexing and enticing, Dr. Collins said, because it almost guarantees that “there probably are pediatric cancer–specific risk genes that we haven’t yet discovered.”

“We have to go deeper than the traditional investigation [of known cancer genes], especially in these tumors that are showing up in very young children,” Dr. Guidry Auvil agreed.

“We've got to look at all of the data with a little bit more of an open mind,” she added.

Overall, the researchers estimated that structural variants are involved in the development of 1% to 6% of neuroblastomas, Ewing sarcomas, and osteosarcomas. That is a rough estimate limited by the relatively small number of children in the study and the exclusion of certain types of structural variants due to technical limitations, the team noted.

No single cause of pediatric cancer

Germline genetic changes are those that are present at birth in every cell in the body. In the study, nearly all of the germline structural variants present in the DNA of children with cancer were inherited from a parent, the researchers found.

But because the parents of these children didn’t have cancer, the finding suggests that there are likely additional factors at play, Dr. Collins explained.

There’s a tendency to think “about the cause and the gene” for cancer, Dr. Gillani said, but it is rarely ever the result of a single cause.

An “obvious next step is to take the holistic composite view of everything that's in these kids’ genomes,” Dr. Collins added, meaning structural variants as well as small mutations and other genetic changes. “Follow-up studies are under way on that avenue,” he said.

Dr. Guidry Auvil agreed, saying, “I think we're doing a disservice to cancer patients if we don't gather as much information as we can about what's going on in these small bodies and start to look at all of these findings collectively,” including “when and where and how these [genetic] events happen” during children’s development.

Understanding and targeting genome instability

The study results hint that children with neuroblastoma, Ewing sarcoma, and osteosarcoma may be prone to acquiring excessive genetic errors, a phenomenon known as genome instability, wrote Jayne Hehir-Kwa, Ph.D., of Princess Máxima Center for Pediatric Oncology in the Netherlands, and Geoff Macintyre, Ph.D., of the Spanish National Cancer Research Center in Spain, in an accompanying perspective.

Like a house with a faulty foundation, cells with genome instability are more prone to accumulating DNA changes, such as structural variants.

During childhood growth spurts, cells are rapidly growing and dividing, Drs. Hehir-Kwa and Macintyre added. If a child’s cells are marked by genome instability, these growth spurts could open the door to acquiring a whole slew of new structural variants, they continued. And that would put those children at greater risk of developing cancer.

Previous studies of childhood cancers, which have found small mutations in genes that normally repair damaged DNA, have also provided evidence that genome instability may be at play.

The upside is that pediatric cancers may be able to be treated with available drugs that target genome instability, Drs. Hehir-Kwa and Macintyre noted. Certain drugs, like PARP inhibitors and platinum-based chemotherapy, work better against cancers that already have a lot of damaged DNA, they explained.

Overall, Drs. Collins and Gillani said, the findings point to a class of genetic changes that are not only driving some childhood cancers but may be targetable in the future.