Inigo Martincorena
@imartincorena.bsky.social
Scientist. Group leader at the Sanger Institute, Cambridge UK. Somatic mutation and selection in normal tissues, cancer and ageing.
The bladder paper above also has one example of an ERCC2 mutant clone acquiring hypermutation.
October 13, 2025 at 9:19 PM
The bladder paper above also has one example of an ERCC2 mutant clone acquiring hypermutation.
I would say it is more the former, relatively uniform mutagenesis with selection. But we saw acquisition of APOBEC in some clones in bladder. And have seen examples of clones with more than one driver. www.science.org/doi/10.1126/... But larger studies with single clone resolution are still needed.
Extensive heterogeneity in somatic mutation and selection in the human bladder
Genome sequencing of healthy human bladder tissue reveals a diverse landscape of mutations that vary between individuals.
www.science.org
October 13, 2025 at 9:18 PM
I would say it is more the former, relatively uniform mutagenesis with selection. But we saw acquisition of APOBEC in some clones in bladder. And have seen examples of clones with more than one driver. www.science.org/doi/10.1126/... But larger studies with single clone resolution are still needed.
Individual mutant clones typically carry 1, sometimes 2 but rarely more, driver mutations, as shown by our previous studies where we had single clone resolution. It is only on aggregate across tens of thousands of clones that you get tens of thousands of driver mutations. I hope that makes sense.
October 13, 2025 at 4:46 PM
Individual mutant clones typically carry 1, sometimes 2 but rarely more, driver mutations, as shown by our previous studies where we had single clone resolution. It is only on aggregate across tens of thousands of clones that you get tens of thousands of driver mutations. I hope that makes sense.
I almost forgot I wrote a short review in 2019 saying this. genomemedicine.biomedcentral.com/articles/10.... The new supplementary notes have useful maths and historical references though.
Somatic mutation and clonal expansions in human tissues - Genome Medicine
Recent sequencing studies on healthy skin and esophagus have found that, as we age, these tissues become colonized by mutant clones of cells carrying driver mutations in traditional cancer genes. This comment summarizes these findings and discusses their possible implications for our understanding of cancer, ageing, and other diseases.
genomemedicine.biomedcentral.com
October 9, 2025 at 5:01 PM
I almost forgot I wrote a short review in 2019 saying this. genomemedicine.biomedcentral.com/articles/10.... The new supplementary notes have useful maths and historical references though.
Thanks Tami! Much appreciated. I agree. A supplementary note is hardly the best place for it. I have been meaning to write a review or two for a long time. But time seems to be eluding me.
October 9, 2025 at 4:09 PM
Thanks Tami! Much appreciated. I agree. A supplementary note is hardly the best place for it. I have been meaning to write a review or two for a long time. But time seems to be eluding me.
In our latest paper, I wrote 2 supplementary notes (5 and 6) to briefly recap classical models, starting with Armitage&Doll and moving onto models with different types of clonal expansions. Some readers may find them of interest. [4/4] static-content.springer.com/esm/art%3A10...
static-content.springer.com
October 9, 2025 at 3:29 PM
In our latest paper, I wrote 2 supplementary notes (5 and 6) to briefly recap classical models, starting with Armitage&Doll and moving onto models with different types of clonal expansions. Some readers may find them of interest. [4/4] static-content.springer.com/esm/art%3A10...
...the observation of large numbers of clones with driver mutations in normal tissues is perfectly consistent with (and indeed predicted by) multistage models of carcinogenesis dating from the 1950s. In the constant rush for new data, we seem to have forgotten invaluable lessons hidden in them [3/4]
October 9, 2025 at 3:29 PM
...the observation of large numbers of clones with driver mutations in normal tissues is perfectly consistent with (and indeed predicted by) multistage models of carcinogenesis dating from the 1950s. In the constant rush for new data, we seem to have forgotten invaluable lessons hidden in them [3/4]
...or (2) the observation of driver mutations in normal tissues "proves" that non-mutational factors are needed to explain cancer (epigenetics, promotion, etc). Of course, many other factors are important, but ... [2/4]
October 9, 2025 at 3:29 PM
...or (2) the observation of driver mutations in normal tissues "proves" that non-mutational factors are needed to explain cancer (epigenetics, promotion, etc). Of course, many other factors are important, but ... [2/4]
Thanks Pierre. I was also struck by that finding... Very unexpected to me. Supplementary notes 5 and 6 try to expand on this, including modelling the types of aggregate clonal growth expected under different models of clonal growth. static-content.springer.com/esm/art%3A10...
static-content.springer.com
October 9, 2025 at 2:31 PM
Thanks Pierre. I was also struck by that finding... Very unexpected to me. Supplementary notes 5 and 6 try to expand on this, including modelling the types of aggregate clonal growth expected under different models of clonal growth. static-content.springer.com/esm/art%3A10...
If you read the preprint, not a lot has changed. But if you didn't, here is a link to the original thread summarising our findings. Since then, NanoSeq has become a workhorse in our lab, unveiling a fascinating landscape of somatic evolution across tissues and diseases. bsky.app/profile/imar...
Resharing here a recent X post. In this preprint, we introduce an improved version of NanoSeq, a duplex sequencing protocol with <5 errors per billion bp in single DNA molecules, and use it to study the somatic mutation landscape of oral epithelium in >1000 people. 1/ www.medrxiv.org/content/10.1...
Somatic mutation and selection at epidemiological scale
As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations ([1][1]–[10][2]. Some of these clones represent a first step towards cancer whereas others may contribu...
www.medrxiv.org
October 8, 2025 at 4:31 PM
If you read the preprint, not a lot has changed. But if you didn't, here is a link to the original thread summarising our findings. Since then, NanoSeq has become a workhorse in our lab, unveiling a fascinating landscape of somatic evolution across tissues and diseases. bsky.app/profile/imar...
Reposted by Inigo Martincorena
So pleased to have the paper out, available here: www.nature.com/articles/s41586-024-08423-8
For me this was discovery science as I had always hoped it would be. A lot of fun, and some proper detective work with plenty of twists & turns on the way. Brief thread below
For me this was discovery science as I had always hoped it would be. A lot of fun, and some proper detective work with plenty of twists & turns on the way. Brief thread below
January 15, 2025 at 9:44 PM
So pleased to have the paper out, available here: www.nature.com/articles/s41586-024-08423-8
For me this was discovery science as I had always hoped it would be. A lot of fun, and some proper detective work with plenty of twists & turns on the way. Brief thread below
For me this was discovery science as I had always hoped it would be. A lot of fun, and some proper detective work with plenty of twists & turns on the way. Brief thread below