Our latest work is now out in Science. Possibly the most fascinating dataset that I have had the privilege of working with. By deeply sequencing normal oesophagus we uncovered a hidden world of mutation and selection acting in our tissues as we age. [1/7] science.sciencemag.org/content/early/…
We found that, although normal oesophagus mutates at ~10-times lower rate than sun-exposed skin, positive selection on cancer-driver mutations is so much stronger that by middle age over half of our oesophagus is colonised by clones carrying driver mutations. [2/7]
In an area of normal oesophagus the size of two postal stamps, we find a staggering 4,000 driver mutations, the equivalent of sequencing ~1,000 cancer genomes. Of these 2,000 mutations occur in the NOTCH1 gene alone. [3/7]
The image below shows a summary representation of what 1cm2 of normal oesophagus looks like in the 9 individuals, sorted by age. We see large differences in burden, clone sizes and even preference to mutate certain genes across patients. [4/7] 
Perhaps the biggest surprise was the extreme frequency of mutations in NOTCH1. This gene is assumed to be a driver gene of oesophageal squamous carcinoma (ESCC) as it is mutated in 10-15% of tumours. Yet we see it mutated in over 40% of normal cells by middle age! [5/7]
While other explanations are possible, this raises questions about the cancer-driving role of NOTCH1 in ESCC. It is theoretically possible that some genes drive benign clonal expansions in normal tissues where cells are less likely to transform to cancer than wildtype cells [6/7]
Yet, to me the most exciting thing about all of this is the realisation of how little we know about somatic evolution outside of cancer. Seeing the prevalence of mutant clones one wonders about their role beyond cancer, in ageing and other diseases. So many opportunities ahead...
This and our previous work is the result of the hard work of many people. A great team effort. So priviliged to work with such amazing and inspiring people! @KSaebParsy @MoritzGerstung @ATJCagan @AbascalFed Peter Campbell, Phil Jones, Mike Stratton, Jo Fowler and so many more
