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- Title
Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.
- Authors
von Loga, Katharina; Woolston, Andrew; Punta, Marco; Barber, Louise J.; Griffiths, Beatrice; Semiannikova, Maria; Spain, Georgia; Challoner, Benjamin; Fenwick, Kerry; Simon, Ronald; Marx, Andreas; Sauter, Guido; Lise, Stefano; Matthews, Nik; Gerlinger, Marco
- 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 their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This reveals 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 are common and parallel evolution occurs 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 show that chromosome 8 gains are early genetic events and that the hypermutator-phenotype remains active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types reveals mutation rates and their timing to determine phylogenetic tree morphologies. Tumours that are deficient in mismatch-repair genes should, in theory, have higher evolvability. Here, the authors explore this theory in gastro-oesophageal tumours.
- Subjects
DNA mismatch repair; BIOLOGICAL evolution; HETEROGENEITY; CANCER; DATA analysis; CHROMOSOMES
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-13915-7