Thread by @S_J_Aitken

We are really excited that our work showing how pervasive lesion segregation shapes cancer genome evolution is published today in @nature.

nature.com/articles/s4158…

Here’s a #tweetorial to explain our #LesionSegregation findings...

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Human cancer genomes are unavoidably confounded by genetic and environmental differences. Such intrinsic heterogeneity hinders 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.
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WGS of mutagen-initiated tumours showed a high burden of point mutations, comparable to human cancers caused by exogenous mutagens, e.g. lung and skin cancer. The tumours are dominated by thymine mutations (“DEN signature”) and driver mutations in the EGFR-RAS-RAF pathway.
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We found something really unexpected: there is a chromosome-scale, strand-asymmetric distribution of mutations. Here are ~60,000 mutations identified in a single tumour... and we find similar Watson-versus-Crick-strand asymmetry of mutations in all 371 tumours genomes.
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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
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Understanding #LesionSegregation means that we can now perform analyses that were previously impossible: accurately measure DNA repair with lesion strand resolution, to quantify oncogenic selection, and to map sister chromatid exchange events.
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#LesionSegregation also predicts the generation of multi-allelic sites and combinatorial genetic diversity, which @craigandersn showed occurs frequently in these tumours. This violates the infinite sites model and challenges Muller's ratchet / Hill-Robertson interference.
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So, do other DNA damaging agents also show #LesionSegregation? Does it occur in human cells? We analysed #openaccess data from @SerenaNikZainal and @icgc_dcc and found that lesion segregation is a pervasive feature of all exogenous mutagens and is evident in human cancers.
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#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.
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Frances, Christine, and I performed thousands of experiments @CRUK_CI @odom_lab. The discovery of #LesionSegregation was by @mst_paralogue. Together with @DrColinSemple, @nlbigas, and @PaulFlicek we formed an international team @LCE_Consortium.
🇬🇧🇪🇸🇮🇳🇩🇪🇪🇪🇬🇷🇳🇱🇮🇪🇱🇻🇺🇸
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We are proud to make our data #openaccess so that you can use them too: WGS @enasequence, RNA-seq @ArrayExpressEBI, tumour histopathology #BioStudies @emblebi.
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Many thanks to the @CRUK_CI core facilities: BRU, Genomics, Bioinformatics, @CI_histocore; @edgenome; and the @emblebi technical services cluster.

And, of course, generous funding from @CR_UK, @ERC_Research, @wellcometrust, @EMBL, @The_MRC, @IRBBarcelona, @NIHRresearch.
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Thanks for reading all about #LesionSegregation - let us know what you think!

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Finally, thank you to Petra Korlevic @petrathepostdoc for this amazing illustration of #LesionSegregation