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

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).

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.

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.

These hypermutant glands are almost exclusively in the antrum of the stomach, chronically inflamed and most importantly, metaplastic. Intestinal metaplasia is a well-known precursor to gastric cancer, but these aren't monoclonal expansions.

We find that gastric glands are clonal units arising from a single stem cell. In non-cancer donors, the mutation rate is 28 SNVs and 2 indels per year. This is mostly true in cancer patients, but some patients have many "hypermutant" glands, with far more mutations than expected.

The lining of the stomach produces acid, and is the origin of stomach cancer, with many risk factors (diet, smoking, H. pylori infection). We used LCM to isolate and sequence normal stomach glands, from gastric cancer patients and non-cancer donors, from Hong Kong, the US and UK.

This effort is made possible by the funders, co-authors, and a large group of passionate and amazing scientists across many institutes! Most importantly, this work would not be possible without the generosity of the donations. @broadinstitute.org @yaleschoolofmed.bsky.social @ohsunews.bsky.social

The dGTEx project extends GTEx across development and across species. We are currently collecting tissues from pediatric donors, marmosets and macaques to generate whole genome, transcriptomic and chromatin profiles to study developmental variation in gene expression and regulation.

The abstract deadline for "Mutations in Time and Space 2025" is in a week! Please register here: broadinstitute.swoogo.com/mits2025

Spread the word! Registration for the "Mutations in Time and Space" conference is open. The meeting is all about the origins, patterns, and consequences of mutations across cells, individuals, populations, species. Abstract submission deadline is Jan 17th broadinstitute.swoogo.com/mits2025/597...