胎盘新基因组研究发现与癌症有深度联系New Genomic Study of Placenta Finds Deep Links to Cancer

New Genomic Study of Placenta Finds Deep Links to Cancer胎盘新基因组研究发现与癌症有深度联系

A patchwork of genomic differences in the placenta may explain the organ’s “live fast, die young” strategy and its connections to cancer.胎盘中基因组差异的拼凑可以解释器官的"活得快,死得早"的策略及其与癌症的联系。

胎盘新基因组研究发现与癌症有深度联系New Genomic Study of Placenta Finds Deep Links to Cancer

New work shows that the human placenta is a mosaic of cells with different genotypes. This heterogeneity may be a consequence of the organ’s protective function.新的研究表明,人类胎盘是具有不同基因型的细胞的马赛克。这种异质性可能是器官保护功能的结果。

胎盘新基因组研究发现与癌症有深度联系New Genomic Study of Placenta Finds Deep Links to Cancer

胎盘新基因组研究发现与癌症有深度联系New Genomic Study of Placenta Finds Deep Links to Cancer

Max Kozlov  April 8,2021

In 2008, while the medical resident Sam Behjati was doing his usual rounds in a hospital maternity ward, a colleague urgently pulled him into a patient’s room, where he saw a mother beaming with joy and swaddling a perfectly healthy newborn. Behjati’s jaw dropped. Only a few months earlier, doctors had given this mother the devastating news that a routine prenatal test — which had analyzed a sample from her placenta — showed that her baby had an extra copy of chromosome 13, a condition typically fatal for newborns. Yet postnatal tests showed that the baby had 23 normal pairs of chromosomes. “I walked away from the room thinking, 'How can that possibly be?’” said Behjati, who is now a geneticist at the Wellcome Sanger Institute.2008年,当医疗居民Sam Behjati在医院产房里做他平常的回合时,一位同事急忙把他拉进病人的房间,在那里他看到一位母亲开心地微笑着,摇摇晃晃地抱着一个完全健康的新生儿。贝贾蒂的下巴掉了下来。就在几个月前,医生们给这位母亲一个毁灭性的消息,一个例行的产前检查——分析了她胎盘的样本——显示她的宝宝有13号染色体的额外拷贝,这种情况通常对新生儿致命。然而产后测试显示,婴儿有23对正常的染色体。"我离开房间时想,'那怎么可能呢?

Behjati had uncovered a case of confined placental mosaicism (CPM), a condition in which patches of the placenta have genomes that don’t match up with that of the fetus — a strange phenomenon given that the placenta and fetus derive from the same fertilized egg. Scientists have known about CPM for decades, and they estimated that it occurs in less than 2% of pregnancies.Behjati发现了一个封闭胎盘马赛克(CPM)的案例,在这种情况下,胎盘的斑块的基因组与胎儿的基因组不匹配——鉴于胎盘和胎儿来自同一受精卵,这是一个奇怪的现象。科学家已经知道CPM几十年了,他们估计它发生在不到2%的怀孕。

But according to a recent study by Behjati and his colleagues in Nature, human placentas routinely consist of a quilt of different genotypes, and this strange heterogeneity may actually play a role in protecting the fetus from genetic harm. The discovery illuminates not only several mysteries about the placenta itself but also some underlying connections to cancer.但是根据贝哈蒂和他的同事最近在《自然》杂志上的一项研究,人类胎盘通常由不同基因型的被子组成,这种奇怪的异质性实际上可能在保护胎儿免受遗传伤害方面发挥作用。这一发现不仅揭示了胎盘本身的几个谜团,也揭示了与癌症的一些潜在联系。

The study painted the clearest picture yet of the genomic landscape of the placenta — and it’s unlike that of any other human tissue ever seen by Behjati, who calls it the “wild west of the human genome.” When they sequenced the DNA of 86 samples from 37 placentas, each set of cells was found to be genetically distinct and chock-full of genetic aberrations typically seen only in aggressive childhood cancers.这项研究描绘了胎盘基因组景观迄今最清晰的画面——它不同于贝哈蒂所见过的任何其他人体组织,贝哈蒂称其为"人类基因组的野生西部"。当他们对来自37个胎盘的86个样本的DNA进行测序时,发现每组细胞在基因上都是不同的,并且充满了遗传畸变,通常只在恶性儿童癌症中出现。

“Every placenta is organized as these big chunks of clones that sit next to each other,” he explained. “It’s like a cobblestone pattern of lots of different tumors that together form the placenta, and that is completely astonishing.”"每个胎盘都组织成这些大块的克隆,彼此坐在一起,"他解释道。"这就像一个鹅卵石图案,由许多不同的肿瘤组成胎盘,这完全是惊人的。

The findings further confirm that the placenta is a biological oddity. Even its origin is peculiar: Placentas are thought to have emerged more than 90 million years ago, when a series of symbiotic retroviruses infiltrated ancient mammals’ genomes and over many generations led to the organ’s formation.研究结果进一步证实胎盘是一种生物学怪胎。甚至它的起源也是奇特的:在9000多万年前,当一系列共生逆转录病毒渗透到古代哺乳动物的基因组中时,胎盘被认为已经出现,并导致该器官的形成。

“It’s this strange organ because mothers invest a huge amount of resources into generating the whole placenta, which they then throw away,” said Steve Charnock-Jones, a reproductive biologist at the University of Cambridge and a co-author of the new study. For decades, biologists have puzzled over the apparent wastefulness of this arrangement: Why would natural selection allow a crucial, resource-intensive feature of mammalian life to be so seemingly inefficient?剑桥大学的生殖生物学家、这项新研究的合著者史蒂夫·查诺克-琼斯(Steve Charnock-Jones)说:"这是一个奇怪的器官,因为母亲们投入了大量资源来生成整个胎盘,然后扔掉了胎盘。几十年来,生物学家一直对这种安排的明显浪费感到迷惑不解:为什么自然选择允许哺乳动物生命的关键、资源密集型特征如此看似低效?

A Genetic 'Dumping Ground’基因"倾倒场"

To try to answer this question, Behjati and his colleagues retraced when and where placental cells originate by comparing patterns of mutations in placental samples with samples from corresponding umbilical cords, which develop from fetal cells. The researchers found that cells separate into fetal and placental lineages earlier than anticipated — in some cases, within the first few cell divisions of the zygote. These findings show that the placenta charts its own path separate from that of the fetus early in pregnancy, explained Derek Wildman, an evolutionary biologist at the University of South Florida who was not involved in the study.为了试图回答这个问题,Behjati和他的同事通过比较胎盘样本中的突变模式和从胎儿细胞中发育的相应脐带的样本来追溯胎盘细胞的起源时间和地点。研究人员发现,细胞比预期更早地分离成胎儿和胎盘血统——在某些情况下,在酶的最初几个细胞分裂中。南佛罗里达大学的进化生物学家德里克·威尔德曼(DerekWildman)解释道,这些发现表明胎盘与怀孕早期胎儿的路径是分开的。

But during those crucial first weeks, when a single genetic defect could derail the pregnancy, the placenta may also act as a “dumping ground” for aberrations. During early development, when some of the dividing cells randomly develop genetic abnormalities, they might get earmarked for the placenta instead of the fetus, Behjati reasoned. His team found evidence for this theory: In one of the biopsies, the researchers observed placental cells with three copies of chromosome 10 — two from the mother and one from the father. But cells in the rest of the placenta and fetus had two copies of the chromosome (both from the mother), which suggested that the error started in the fertilized egg but was later corrected.但在那些关键的头几周,当一个单一的遗传缺陷可能破坏怀孕,胎盘也可能作为一个"倾倒场"的畸变。贝哈提说,在早期发育过程中,当一些分裂细胞随机出现遗传异常时,它们可能会被指定用于胎盘而不是胎儿。他的团队为这一理论找到了证据:在一次活检中,研究人员观察了10号染色体的三个拷贝的胎盘细胞——两个来自母亲,一个来自父亲。但胎盘和胎儿其余部位的细胞有两个染色体副本(均来自母亲),这表明错误始于受精卵,但后来被纠正。

Patches of the placenta continue to carry on these early mutations — a living archive of genetic defects from the first days of pregnancy — while the fetus remains unharmed. But that’s no problem for the placenta, Wildman hypothesizes, because “it’s not constrained by the necessity to successfully produce an organ that’s going to live for 85 years.” The placenta may not have the same genetic checks and balances that other human cells do because of its inherent transience, he said.胎盘的斑块继续进行这些早期突变——这是怀孕初期遗传缺陷的活档案——而胎儿仍然安然无恙。但是,威尔德曼推测,这对胎盘来说没有问题,因为"成功产生一个能活85年的器官并不局限。他说,胎盘可能不像其他人类细胞那样具有基因制衡作用,因为它具有固有的瞬变性。

Another possible explanation for these mutations, Behjati said, is that the placenta must outpace the growth of the fetus for the first 16 weeks of human pregnancy, so it may be worth racking up mutations as it balloons inside the uterus. It can “live fast and die young,” as Behjati put it.Behjati说,这些突变的另一个可能解释是胎盘在人类怀孕的头16周必须超过胎儿的生长,所以当胎盘在子宫内膨胀时,它也许值得积累突变。正如贝贾蒂所说,它可以"活得快,死得早"。

Wendy Robinson, a medical geneticist at the University of British Columbia who studies early human development, said that it’s an interesting theory, but she disagreed with the notion that the placenta is merely the genetic garbage pail for the fetus. “There’s very rapid cell divisions that occur early in pregnancy, and that probably imposes a strong selection against cells that just can’t keep up, and so only the good cells will contribute [to the fetus],” she said. “So, it’s not that you’re shunting the bad cells to the placenta — and I know it’s semantics — but it’s that you’re selecting for the good cells in the baby and leaving everything else behind.”研究早期人类发育的不列颠哥伦比亚大学的医学遗传学家温迪·罗宾逊说,这是一个有趣的理论,但她不同意胎盘只是胎儿的基因垃圾桶的观点。她说:"在怀孕早期就出现了非常快速的细胞分裂,这可能强加于无法跟上的细胞,因此只有好的细胞才能(对胎儿)做出贡献。"所以,并不是说你把坏细胞分流到胎盘上——我知道这是语义上的——而是你选择的是婴儿的好细胞,把其他一切都抛在脑后。

The Normal Abnormal Cells正常异常细胞

Regardless of the placenta’s role, the newly uncovered heterogeneity underscores just how miraculous it is that the placenta can evade detection and destruction by the maternal immune system, said Wildman. “You would think that the variant genes, which differ from the maternal genome, would be recognized by the maternal immune system,” he said.威尔德曼说,不管胎盘的作用如何,新发现的异质性突显出胎盘能够逃避母体免疫系统的检测和破坏是多么神奇。"你会认为,与母体基因组不同的变异基因会被母体免疫系统识别,"他说。

Researchers have long noted similarities between cancers and the placenta — in how they evade the immune system, their invasion tactics and the set of chemical tags on their cells’ DNA that direct the activity of their genes. The two behave alike, too, Robinson said: For a successful pregnancy, the placenta must invade the uterine lining of the mother, tap into the mother’s blood supply and create its own network of blood vessels — all of which cancerous cells do as well.长期以来,研究人员一直注意到癌症和胎盘之间的相似性——它们如何逃避免疫系统、入侵策略以及细胞DNA上指示其基因活性的一组化学标记。罗宾逊说:为了成功怀孕,胎盘必须侵入母亲的子宫内衬,利用母亲的血液供应,并建立自己的血管网络——癌细胞也这样做。

Given these similarities, “people who study cancer should be very interested in this study,” said Yoel Sadovsky, the executive director of the Magee-Womens Research Institute in Pittsburgh who studies placental genetics. “It may suggest that childhood cancers have the same primitive things as the placenta that allow abnormal cells to propagate, but not in the normal embryonic tissue.”鉴于这些相似之处,"研究癌症的人应该对这项研究非常感兴趣,"匹兹堡马吉-妇女研究所研究胎盘遗传学的执行主任约尔·萨多夫斯基说。它可能表明儿童癌症的原始物质与胎盘相同,胎盘允许异常细胞繁殖,但在正常的胚胎组织中除外。

Although the placenta and cancers are both invasive, there is a crucial difference: The placenta normally knows when to stop growing. (A very rare condition known as placenta accreta occurs if the placenta continues to invade the uterine muscle or nearby organs like the bladder.) While fetal growth accelerates rapidly during the third trimester, the most intense growth for the placenta takes place in the first trimester, said Charnock-Jones, adding that it would be problematic if the placenta continued to act as a tumor and drained valuable resources from the fetus during the third trimester.虽然胎盘和癌症都是侵入性的,但有一个关键的区别:胎盘通常知道什么时候停止生长。(如果胎盘继续侵入子宫肌肉或膀胱等附近器官,则会发生一种非常罕见的称为胎盘累积的情况。Charnock-Jones说,虽然胎儿生长在第三个三个月中迅速加速,但胎盘最强烈的生长发生在头三个月,并补充说,如果胎盘继续充当肿瘤,并在妊娠三个月期间从胎儿中排出宝贵的资源,那将是有问题的。

“Not only did we find cancer-causing mutations, but we also actually found something that genomically looks like a perfectly normal cancer with very odd genetic signatures and copy number changes,” Behjati said.Behjati说:"我们不仅发现了致癌突变,而且实际上还发现了一种在基因组学上看起来完全正常的癌症,具有非常奇怪的基因特征和拷贝数变化。

“A cell can be normal despite all of that, and I find that quite incredible.”"尽管如此,一个细胞可能是正常的,我觉得这相当令人难以置信。

2021-04-13

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