Inigo Martincorena

🚨 New paper from our lab just published in Nature🚨

www.nature.com/articles/s41...

Discover how 🌱 tumour formation is shaped by tissue context from the very beginning. Cancer is not driven by genetics alone

✨Fantastic team led by Greta Skrupskelyte, Eduardo Rojo, @hariajith.bsky.social

Somatic genomics as a discovery engine for biomedicine Somatic mutations, or genetic changes occurring in cells after conception, are widespread in healthy tissues but are conventionally viewed as signs of…

Somatic genomics as a discovery engine for biomedicine - a Perspective in Cell
www.sciencedirect.com/science/arti...

$125m awarded to five visionary teams $125m awarded to five visionary teams

📰 News announcement! www.cancergrandchallenges.org/new-teams-an...

We’re thrilled to welcome five world-leading scientific teams, each awarded up to £20 million, to take on some of the toughest unanswered questions in #CancerResearch.

Find out more about the teams and their challenges.

Ancestry and somatic profile indicate acral melanoma origin and prognosis - Nature Analysis of the somatic and transcriptomic profile of 123 acral melanoma samples from Mexican patients helps understand tumour origins and prognosis, and highlights the importance of including samples...

We are very happy to see our study finally appear online @nature.com! This has been work of nearly 10 years in collaboration with the National Institute of Genome Medicine 🇲🇽, the National Cancer Institute 🇲🇽, the @sangerinstitute.bsky.social and others ⬇️

www.nature.com/articles/s41...

A small polymerase ribozyme that can synthesize itself and its complementary strand The emergence of a chemical system capable of self-replication and evolution is a critical event in the origin of life. RNA polymerase ribozymes can replicate RNA, but their large size and structural ...

How could a simple self-replicating system emerge at the origins of life? RNA polymerase ribozymes can replicate RNA, but existing ones are so large that their self-replication seems impossible. Could they be smaller?

Excited to share our latest work in @science.org on a new small polymerase.
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A beautifully crafted summary of the extraordinary discovery in the lab of my @mrclmb.bsky.social colleague @philholliger.bsky.social of a tiny RNA that can replicate RNA.

Fully funded postdoc position in my team. CRUK and Wellcome Sanger Institute. Want to work on lung cancer + functional genomics?
Only 1 more week to apply!💥

The specificity and structure of DNA cross-linking by the gut bacterial genotoxin colibactin Accumulating evidence has connected the chemically unstable, DNA-damaging gut bacterial natural product colibactin to colorectal cancer, including the identification of mutational signatures that are ...

Colibactin-DNA interstrand crosslinks structure reveals DNA-damaging acitivity of colibactin that is linked to colorectal cancer #MicroSky www.science.org/doi/10.1126/...

Virus-induced APOBEC3 transmutagenesis in bladder cancer initiation A model for hit-and-run viral carcinogenesis in the bladder.

What causes bladder cancer initiating mutations?
Our paper in Science Advances asks the question: can BK virus infections of normal urothelium lead to the APOBEC3 mutational signatures found in bladder cancers?
We found that they can!

To me the biggest open question is the extent to which this phenomenon (particularly clonal selection of selfish clones) contributes (or could even drive) diseases and age-related phenotypes that are not currently thought of in somatic mutation terms. Expect many surprises in the next few years.

High burden and pervasive positive selection of somatic mutations in normal human skin Sun-exposed but physiologically normal human skin harbors an unexpectedly high number of cancer-causing mutations. [Also see Perspective by Brash]

Over a decade in fact! www.science.org/doi/10.1126/.... The rates and patterns of mutations across many tissues are reasonably well known by now, but it is exciting to finally have reliable single-cell DNA (+RNA) sequencing technologies.

The bladder paper above also has one example of an ERCC2 mutant clone acquiring hypermutation.

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.

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.

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.

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.

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]

...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]

A short thread. For years, I have been surprised by how much confusion our discovery of clones carrying cancer-driver mutations in normal tissues has caused in the cancer community. Typical questions like: (1) if you see these mutations in normal cells, are they really cancer drivers?... [1/4]

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...

Thanks Jeff!

Sex and smoking bias in the selection of somatic mutations in human bladder - Nature Sex bias and association with smoking history identified in the landscape of driver mutations and clonal expansions in normal human bladder tissue may explain the higher bladder cancer risk in men and smokers.

🚨 New paper alert!

Sex and smoking bias in the selection of somatic mutations in human bladder

www.nature.com/articles/s41...

by @raquelbmi.bsky.social, @ferriol.bsky.social et al (in collaboration with Rosana Risques lab in @uwmedicine.bsky.social)

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...

Somatic mutation and selection at population scale - Nature A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Our latest work is out in Nature today. In this paper, 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 www.nature.com/articles/s41...

Sperm sequencing reveals extensive positive selection in the male germline - Nature A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

Now published! Our paper on:
(1) Accurate sequencing of sperm at scale
(2) Positive selection of spermatogenesis driver mutations across the exome
(3) Offspring disease risks from male reproductive aging
[1/n]
www.nature.com/articles/s41...

I am speaking at #AACR25 this afternoon on our latest work on somatic mutations in normal tissues. If you are attending AACR, feel free to drop by and say hello.
brnw.ch/21wRUZZ

If you are looking for an exciting postdoc position, please see below! Adrian Baez Ortega (a former member of the group) is starting an independent group at the University of Cambridge on the evolution of transmissible cancers and is recruiting. tinyurl.com/pdra-cambridge

The somatic mutation landscape of normal gastric epithelium - Nature Whole-gene sequencing of&nbsp;microdissected&nbsp;gastric glands from individuals with and without gastric cancer reveals distinct patterns&nbsp;of somatic mutations and provides insights into influen...

The stomach is an organ unique in its function, environment and exposures. How does this affect the mutations that normal cells in the stomach acquire? What does this reveal about the origins of stomach cancer? These questions and more in our @nature.com paper:
www.nature.com/articles/s41...