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

Author

Listed:
  • Katharina von Loga

    (The Institute of Cancer Research
    The Royal Marsden Hospital)

  • 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
    University Hospital Fuerth)

  • 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
    The Royal Marsden Hospital)

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.

Suggested Citation

  • Katharina von Loga & Andrew Woolston & Marco Punta & Louise J. Barber & Beatrice Griffiths & Maria Semiannikova & Georgia Spain & Benjamin Challoner & Kerry Fenwick & Ronald Simon & Andreas Marx & Gui, 2020. "Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13915-7
    DOI: 10.1038/s41467-019-13915-7
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