Last but not least, if you're interested in somatic mutations, new technologies and computational genomics - we're hiring a postdoc in my brand new lab
@emblebi.bsky.social!

Reach out if interested or you have any questions, and apply here: embl.wd103.myworkdayjobs.com/en-US/EMBL/j...

This effort would be impossible without the work of many hundreds of people, including the scientists, the NIH staff, and - of course - the donors and their family. A very exciting time to study somatic evolution and I can't wait to see what the next years bring.

SMaHT will generate massive amounts of data, including short-read, long-read, duplex, single cell DNA, and donor specific assemblies, and much more. Check out our stellar data platform (data.smaht.org), courtesy of our Data Analysis Center in Peter Park's lab - watch this space for future data!

Underpinning the efforts of the Network is a set of 150 donors from across the US and age range, collected by the NDRI, with many tissues samples for each donor - an absolutely unique collection and momentous effort. Also more info at our consortium website: smaht.org

The SMaHT Network, funded by the NIH Common Fund, has over 300 members from over 50 different institutions all working together on developing new tools and technologies to detect somatic variation, analysing the data in the best way possible, and generating a reference catalog of mosaicism

Thanks again for coming over to speak! It was an amazing talk

Thanks very much, Daniel!

Read ‘The somatic mutation landscape of normal gastric epithelium’ from @sangerinstitute.bsky.social, @broadinstitute.org, The University of Hong Kong & others in @nature.com ⤵️

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

Thanks to all the donors and their families for making this study possible. And many thanks to Grace Collord, Peter Campbell, @imartincorena.bsky.social , SY Leung, Mike Stratton and all other co-authors. @broadinstitute.org @sangerinstitute.bsky.social

In short, the normal stomach shows a landscape of somatic mutations with many differences from those of other organs. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states

Because we used the LCM approach, we can map these driver clones to their location in tissues, which reveals expansions of mutant clones and local selective pressures. We find three CTNNB1 mutant clones right next to one another, rather than evenly distributed.

Lastly, the stomach also shows a rich landscape of driver mutations, most notably in epigenetic modifiers (ARID1A, ARID1B, KDM6A) and surprisingly inactivating mutations in CTNNB1 (unlike the activating ones observed in cancer).

Glands with trisomies were not associated with a specific stomach region, and their incidence does not linearly increase with age, but are associated with severe chronic inflammation. It's plausible these are a consequence of an exposure, a pathogen or otherwise, long before the time of sampling.

Intriguingly, these trisomies happen multiple times in the same donor, with different alleles amplified. In one case, we found trisomies in 9 of 12 glands sampled. Timing analysis shows these all happened around the same time, suggesting a sudden burst or selective advantage.

The most surprising finding, however, comes from the CNVs in the stomach. We find extraordinarily high rates of somatic whole-chromosome gains/trisomies in the stomach, mostly of chrs 20 and 13, highly concentrated in a few patients.

While SBS17 is very common in gastric cancer, we only find it very rarely in normal glands, and only in very low proportions. So while stomach cells can get exposed to SBS17, high levels of SBS17 seem to be exclusive to overt cancer.

The mutational signatures are mostly SBS1, SBS5 and SBS18, like other epithelial tissues. Metaplastic glands have much more SBS1 and SBS18 (ROS), and indels linked to polymerase slippage. These are also dominant in intestinal glands, so may suggest a “rewiring” of the mutation rate.