Twins who tragically died from the same rare cancer shortly after birth have helped scientists understand how the condition can spread from one to the other in utero. Their analysis of the twins鈥� DNA has also led to a radical rethink about how identical twins split apart after conception.
鈥淚t鈥檚 an incredibly awful thing to have happened, but their mother was very clear that we had to learn something from it, and has made this amazing gift to science,鈥� says at the Wellcome Sanger Institute in Cambridge, UK. 鈥淚t鈥檚 meant that we鈥檝e been able to provide a little bit of an answer [to] what happened to these babies, but also gleaned a fundamental insight into twinning.鈥�
The twins, Amelia and Amaya, were delivered by caesarean section at 34 weeks鈥� gestation after one was found to have a facial mass during a scan. When they were born, they were both discovered to have cancer in multiple locations, and died soon afterwards. 鈥淕etting cancer as a newborn is extraordinarily rare,鈥� says Behjati.
Advertisement
This led to the question of whether the cancer arose in one twin and spread to the other, or developed separately, perhaps due to a shared inherited mutation that predisposed both to the condition.
To investigate, Behjati and his colleagues performed whole-genome sequencing on 45 samples of cells collected from the twins鈥� organs, placenta and tumours in a post-mortem analysis.
Although the twins started with the same DNA, it became slightly different once they split apart, due to the natural build-up of mutations over time. This meant the researchers could spot the difference between the sisters鈥� cells and estimate the timing of their cancer development.
They found that a mistaken fusion of two genes, MN1 and ZNF341, occurred in one of the twins, referred to in the study as twin A, around the end of the first trimester, for unknown reasons. This genetic rearrangement led to the growth of a tumour on her face, as well as others in her brain, liver and other organs. The tumours were identified as soft tissue sarcomas, rare cancers that can affect skin, nerves, blood vessels, muscles and fat.
Around the end of the second trimester, tumour cells from twin A spread to her sister, referred to as twin B. This led twin B to develop tumours on her skin and in her brain that were composed of twin A鈥檚 tumour cells.
The cancer probably spread via the twins鈥� shared circulation, says Behjati. 鈥淲hen you share a placenta, you inevitably end up sharing blood vessels,鈥� he says. The tumour in twin B appears to have formed from just one cancer cell from twin A that crossed over and then multiplied, he says.
One of the most surprising findings was how the twins initially split apart after conception. It has long been assumed that identical twins come from an embryo that splits in half, which would mean that half of the embryo鈥檚 cells became twin A and the other half became twin B.
Instead, the researchers discovered that just one cell in the embryo developed into twin A, while all the other cells became twin B and the entire placenta. This is curious, because you would assume that the placenta would contain an even mix of twin A and B鈥檚 cells, says Behjati. 鈥淚f you go to placenta researchers and say, 鈥楬ere鈥檚 this pregnancy where one twin made all the placenta鈥�, they鈥檙e going to say, 鈥極h, that鈥檚 interesting鈥�,鈥� says Behjati.
The team is now setting up a study to 鈥渓ook into twinning more systematically, because the questions this raises are really quite fascinating鈥�, he says.
Nature Communications
