Thread by @S_J_Aitken

We are really excited to share our work on how Pervasive lesion segregation shapes cancer genome evolution @biorxivpreprint.

Here’s a #tweetorial to explain our #LesionSegregation findings...
biorxiv.org/content/10.110…
Thread, 1/11

Human cancer genomes are unavoidably confounded by genetic and environmental differences. Such intrinsic heterogeneity confounds our ability to disentangle biases of DNA damage and repair. So we used an in vivo oncogenesis model to re-run cancer evolution hundreds of times.
2/11

WGS of these mutagen-initiated tumours had a high burden of point mutations, comparable to cancers caused by exogenous mutagens, eg lung and skin cancer. The tumours are dominated by Thymine mutations - the “DEN signature” - and driver mutations in the EGFR/RAS/RAF pathway.
3/11

We found something really unexpected: there is a chromosome-scale, strand-asymmetric distribution of mutations. Here are the ~60,000 mutations from a single tumour - and we find similar asymmetry in all 371 tumours genomes.
4/11

We explain this using the #LesionSegregation model.
- Mutagens generate lesions on each DNA strand and segregate during replication.
- Daughter cells have non-overlapping lesions, which are then resolved into full mutations.
- Lineages with drivers undergo clonal expansion.
5/11

Understanding #LesionSegregation means that we can now accurately measure DNA repair with lesion strand resolution, to quantify oncogenic selection, and to map sister chromatid exchange events.
6/11

#Lesionsegregation also predicts the generation of multi-allelic sites and combinatorial genetic diversity - which does happen! This violates the infinite sites model and challenges Muller's ratchet / Hill-Robertson interference.
7/11

So, do other DNA damaging agents also show #LesionSegregation? Does it occur in human cells and cancers? We re-analysed #openaccess data from ICGC (thank you!) and found that #LesionSegregation is a pervasive feature of all exogenous mutagens and is evident in human cancers.
8/11

#LesionSegregation is actually a pretty intuitive concept - but the discovery of this pervasive lesion segregation profoundly revises our understanding of how the architecture of DNA repair and clonal proliferation can conspire to shape the cancer genome.
9/11

The discovery and analysis of #LesionSegregation was from @mst_paralogue, with @DrColinSemple, @PaulFlicek, and @nlbigas. All of the experimental work was done in Duncan Odom’s lab @CRUK_CI. Together we formed a team of scientists as the #LCEConsortium.
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10/11

Thanks for reading - let us know what you think!

#LCEConsortium
11/11