Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

von Loga, K.; Woolston, A.; Punta, M.; Barber, L. J.; Griffiths, B.; Semiannikova, M.; Spain, G. J.; Challoner, B.; Fenwick, K.; Schiffmann, H.; Marx, A.; Sauter, G.; Lise, S.; Matthews, N.; Gerlinger, M.

doi:10.1101/755199

bioRxiv · 10.1101/755199

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

von Loga, K.·Woolston, A.·Punta, M.·Barber, L. J.·Griffiths, B.·Semiannikova, M.·Spain, G. J.·Challoner, B.·Fenwick, K.·Schiffmann, H.·Marx, A.·Sauter, G.·Lise, S.·Matthews, N.·Gerlinger, M.

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Abstract

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but how these cancers evolve has not been investigated in detail. We applied multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This revealed extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations were common and parallel evolution occurred in RAS, PIK3CA, SWI/SNF-complex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs showed that chromosome 8 gains were among the earliest genetic events and that the hypermutator-phenotype remained active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types revealed mutation rates and their timing as major determinants of phylogenetic tree morphologies.

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von Loga, K., Woolston, A., Punta, M., Barber, L. J., Griffiths, B., Semiannikova, M., Spain, G. J., Challoner, B., Fenwick, K., Schiffmann, H., Marx, A., Sauter, G., Lise, S., Matthews, N., Gerlinger, M.. 2019-09-02. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. https://doi.org/10.1101/755199

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