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

Katharina von Loga, Andrew Woolston, Marco Punta, Louise J. Barber, Beatrice Griffiths, Maria Semiannikova, Georgia Spain, Benjamin Challoner, Kerry Fenwick, Ronald Simon, Andreas Marx, Guido Sauter, Stefano Lise, Nik Matthews and Marco Gerlinger ()
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Katharina von Loga: The Institute of Cancer Research
Andrew Woolston: The Institute of Cancer Research
Marco Punta: The Institute of Cancer Research
Louise J. Barber: The Institute of Cancer Research
Beatrice Griffiths: The Institute of Cancer Research
Maria Semiannikova: The Institute of Cancer Research
Georgia Spain: The Institute of Cancer Research
Benjamin Challoner: The Institute of Cancer Research
Kerry Fenwick: The Institute of Cancer Research
Ronald Simon: University Medical Center Hamburg-Eppendorf
Andreas Marx: University Medical Center Hamburg-Eppendorf
Guido Sauter: University Medical Center Hamburg-Eppendorf
Stefano Lise: The Institute of Cancer Research
Nik Matthews: The Institute of Cancer Research
Marco Gerlinger: The Institute of Cancer Research

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13915-7

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