Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.
Katharina von LogaAndrew WoolstonMarco PuntaLouise J BarberBeatrice GriffithsMaria SemiannikovaGeorgia SpainBenjamin R ChallonerKerry FenwickRonald SimonAndreas MarxGuido SauterStefano LiseNik MatthewsMarco GerlingerPublished in: Nature communications (2020)
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.
Keyphrases
- papillary thyroid
- single cell
- squamous cell
- electronic health record
- copy number
- genome wide
- climate change
- big data
- childhood cancer
- type diabetes
- transcription factor
- wild type
- hiv infected
- gene expression
- dna methylation
- lymph node metastasis
- mass spectrometry
- metabolic syndrome
- skeletal muscle
- deep learning
- single molecule