Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.
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Authors
von Loga, K
Woolston, A
Punta, M
Barber, LJ
Griffiths, B
Semiannikova, M
Spain, G
Challoner, B
Fenwick, K
Simon, R
Marx, A
Sauter, G
Lise, S
Matthews, N
Gerlinger, M
Woolston, A
Punta, M
Barber, LJ
Griffiths, B
Semiannikova, M
Spain, G
Challoner, B
Fenwick, K
Simon, R
Marx, A
Sauter, G
Lise, S
Matthews, N
Gerlinger, M
Document Type
Journal Article
Date
2020-01-16
Date Accepted
2019-12-05
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.
Citation
Nature communications, 2020, 11 (1), pp. 139 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Translational Oncogenomics