High-resolution genetic sequencing of immune cells has provided new insights into the process of mutation that can lead to lymphoma, UK researchers have reported.
In the study, published in Nature, researchers from the Wellcome Sanger Institute and the University of York created a new protocol that allowed them to grow and sequence colonies of B- and T-cells from a single cell.
They found that the mutations seen in healthy B-cells were largely similar to those seen in cancerous B-cells, which suggests the development of the cancer arises from the same mutational processes.
Understanding more about the factors that mean these mutations cause cancer in some cells but not others could help them to establish the origins of the disease, the researchers say.
Mutations in lymphocytes may also influence ageing and other diseases of the immune system. Finding out more about when and how these occur over a person’s lifespan adds to our knowledge about what happens during the ageing process.
The team sequenced genomes from more than 700 normal B and T cells across seven donors aged from 0 to 81 years.
The researchers found that, while normal genetic mutation is mostly targeted to the genes for antibodies, a surprising amount of collateral damage occurs elsewhere in the genome. They say these off-target mutations can lead to lymphocytes becoming cancerous and developing into lymphoma.
They also found that, as lymphocytes spread through the body to survey for infections, they are exposed to additional DNA damaging agents, which can further increase the number of mutations. For example, some variation was caused by DNA damage from sunlight as lymphocytes passed through the skin surveying for infections.
First author Dr Heather Machado, from the Wellcome Sanger Institute, said: “The adaptive immune system changes a lot as we age, but previously it has not been possible to study this in the same level of detail as we have achieved here.
“Our research is another step towards understanding how mutations in lymphocytes accumulate over time and the impact that these have on the ageing process. The protocol we have developed in order to expand cells can also be applied to other areas of research, and we hope that it will be as valuable to other scientists as it is to us.”
Co-senior author Dr David Kent, from the York Biomedical Research Institute at the University of York, said: “Our research suggests that even though lymphocytes play the same role throughout the body, the mutations that they acquire are linked to their specific tissue environments.
“These environments could play a larger role in the development of certain lymphomas than inherited mutations. Understanding these processes in greater detail may be able to help shed light on why some of these cells go on to develop into cancer, while others don’t.”
Dr Peter Campbell, co-senior author from the Wellcome Sanger Institute, added: “Our research begins to fill in the missing gaps in knowledge around how mutations in the adaptive immune system feed into ageing.
“By sequencing around 700 lymphocyte genomes, we have started to build a better picture of the mutational processes that happen over time, and how these relate to the development of lymphoma. While more research is needed, this research gives a strong foundation for further studies into this area.”
Machado HE, Mitchell E, Øbro NF, Kübler K, Davies M, Leongamornlert D, Cull A, Maura F, Sanders MA, Cagan ATJ, McDonald C, Belmonte M, Shepherd MS, Vieira Braga FA, Osborne RJ, Mahbubani K, Martincorena I, Laurenti E, Green AR, Getz G, Polak P, Saeb-Parsy K, Hodson DJ, Kent DG, Campbell PJ. (2022) “Diverse mutational landscapes in human lymphocytes.” Nature, doi: 10.1038/s41586-022-05072-7
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