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Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer
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DOI：10.1038/s41467-019-13915-7.png)
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Abstract
En 中文
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.
Keywords:
MUTATIONAL PROCESSES
MICROSATELLITE INSTABILITY
CLONAL HETEROGENEITY
PD-1 BLOCKADE
CHROMOSOME 8Q
COPY NUMBER
RESISTANCE
SIGNATURES
GENOME
ANNOTATION
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15.7
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