1. Author Correction: Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer
- Author
-
Maria Semiannikova, Marco Punta, Andrew Woolston, Marco Gerlinger, Benjamin Challoner, Guido Sauter, Beatrice Griffiths, Stefano Lise, Ronald Simon, Georgia Spain, Andreas H. Marx, Katharina von Loga, Nik Matthews, Kerry Fenwick, and Louise J. Barber
- Subjects
medicine.medical_specialty ,Esophageal Neoplasms ,Science ,Tumour heterogeneity ,General Physics and Astronomy ,Adenocarcinoma ,Gastroenterology ,DNA Mismatch Repair ,General Biochemistry, Genetics and Molecular Biology ,Gastro oesophageal cancer ,Gastrointestinal cancer ,Genetic Heterogeneity ,Stomach Neoplasms ,Internal medicine ,Cancer genomics ,Medicine ,Humans ,Exome ,lcsh:Science ,Author Correction ,Cancer genetics ,Phylogeny ,Cancer ,Immune Evasion ,Mismatch Repair Endonuclease PMS2 ,Multidisciplinary ,business.industry ,General Chemistry ,DNA-Binding Proteins ,MutS Homolog 2 Protein ,Phenotype ,Mutation ,DNA mismatch repair ,lcsh:Q ,Immunotherapy ,business ,MutL Protein Homolog 1 ,Genes, Neoplasm - 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.
- Published
- 2020