Researchers based at the Wellcome Sanger Institute and the University of Cambridge have produced the first high resolution map of the genetic architecture of the placenta, publishing their findings in Nature. To their surprise, the team discovered that the genetic structure of the placenta contains similar DNA faults (mutations) to those frequently seen in children’s cancers.
But the placenta still functions entirely as it should.
“What we found completely blew our socks off.” – Dr Sam Behjati
Dr Sam Behjati is one of the lead researchers involved in the project. Behjati is a paediatrician scientist who has recently been funded as part of the Cancer Research UK–Children with Cancer UK Innovation Awards. He spoke to us about what the latest results could mean for the future of children and young people’s cancer research.
Retracing steps to the first cell division
In the earliest days of pregnancy, a fertilized egg will embed itself into the wall of the uterus and begin dividing from one cell into many. Cells will begin to specialise into various cell types – a process known as differentiation – to create the foetus, with some splitting off to form the placenta.
“Magdelena Zernicka-Goetz, an eminent embryologist, first put out this idea in 2005 that when the egg divides, one cell makes most of the embryo and the other cell makes most as a placenta,” explains Behjati. “And so we were interested in that very first cell division, and whether it’s got something to do with the ability of the fertilised egg to get rid of genetically abnormal cells.”
The team at the Wellcome Sanger Institute retraced the evolution of cells back to the very first cell divisions of the fertilised egg. They read the entire DNA sequence, using a technique called whole genome sequencing, of cells from 42 different placentas, with samples taken from distinct areas of each placenta.
What they found was something that has never been seen before.
The ‘wild west’ of the human genome
“What we found completely blew our socks off,” says Behjati.
“We sequenced a pea sized chunk of placenta, and found it has the genetic structure similar to a tumour. And then we took another chunk from a different area of the placenta, and it’s structured like another, independent tumour.”
What the team discovered is that if a cell has a mutation, for example, an abnormal number of chromosomes, it gets pushed to the outside of the embryo, and ends up in the placenta. “The placenta is kind of the ‘wild west’ of the human genome, it genuinely does not seem to care how riddled with mutations it is,” says Behjati.
The team also found that, when you looked at the DNA of cells in different parts of the placenta, they all looked different, forming distinct clusters of cells. This process is very similar to the formation of a cancer, which often begins with changes in a single cell.
The next step was for the team to analyse the mutations in more detail.
In a number of the biopsies, they came across a few very specific mutations that are known to be the drivers of a number of children’s cancers.
“The mutation signature that we saw in the placenta cells is one of childhood cancer, specifically of neuroblastoma and rhabdomyosarcoma, which has never been seen in normal tissue before. It was completely unexpected,” explains Behjati.
Back to cancer
The results of the study have wide-ranging implications, as the Sanger Institute explains. But what does all this mean for the future of children’s cancer research?
“The reason I study mutations in normal tissue is because mutations are the cause of cancer. Therefore, we need to understand a lot about mutations in order to understand cancer,” explains Behjati.
He adds that it was surprising that you can get an organ that contains many cancer mutations, but that functions entirely as it’s supposed to.
“Really what we need to get down to is that a childhood cancer and a human placental tissue have got the same genetic defects, yet one is a cancer and the other is not.
“We are getting closer and closer to pinning down what the difference is. Initially we thought the difference was just the mutations. But it is now clear the difference isn’t just the mutations, it’s something else, plus the mutations.”
Professor Christine Harrison is part of another team who has recently received an Innovation Award, looking into the role of aneuploidy to treat children’s cancers in the development of childhood cancers and how it may be exploited to improve treatment.
Aneuploidy is when a cell has one or more extra or missing chromosomes. Aneuploidies are often found in the cancer cells of children and young people with different types of cancer, and was also seen in the genetic structure of the placenta.
“This fascinating research by Dr Behjati and his team has discovered approximately half of the placental samples studied showed evidence of chromosomal gains and losses (aneuploidies). These findings are unique for non-cancerous human tissue, specifically the changes in aneuploidy,” explains Harrison.
Harrison adds that the results from this paper could have implications for the future of chromosome and childhood cancer research.
“Some of the genetic changes reported here are prevalent in childhood cancer, in particular the aneuploidies.” She adds that studying the changes seen in the placenta in larger studies may help to provide clues about the development of certain cancers, particularly those that arise in very young children, and provide information towards how these cancers may be prevented.
Lilly
