TY - JOUR T1 - Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer JF - bioRxiv DO - 10.1101/755199 SP - 755199 AU - Katharina von Loga AU - Andrew Woolston AU - Marco Punta AU - Louise Barber AU - Beatrice Griffiths AU - Maria Semiannikova AU - Georgia Spain AU - Benjamin Challoner AU - Kerry Fenwick AU - Ronald Simon AU - Andreas Marx AU - Guido Sauter AU - Stefano Lise AU - Nik Matthews AU - Marco Gerlinger Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/02/755199.abstract N2 - 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-naïve 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. ER -