Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer
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Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. / von Loga, Katharina; Woolston, Andrew; Punta, Marco; Barber, Louise J; Griffiths, Beatrice; Semiannikova, Maria; Spain, Georgia; Challoner, Benjamin; Fenwick, Kerry; Simon, Ronald; Marx, Andreas; Sauter, Guido; Lise, Stefano; Matthews, Nik; Gerlinger, Marco.
In: NAT COMMUN, Vol. 11, No. 1, 16.01.2020, p. 139.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer
AU - von Loga, Katharina
AU - Woolston, Andrew
AU - Punta, Marco
AU - Barber, Louise J
AU - Griffiths, Beatrice
AU - Semiannikova, Maria
AU - Spain, Georgia
AU - Challoner, Benjamin
AU - Fenwick, Kerry
AU - Simon, Ronald
AU - Marx, Andreas
AU - Sauter, Guido
AU - Lise, Stefano
AU - Matthews, Nik
AU - Gerlinger, Marco
PY - 2020/1/16
Y1 - 2020/1/16
N2 - 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.
AB - 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.
KW - Adenocarcinoma/genetics
KW - DNA Mismatch Repair
KW - DNA-Binding Proteins/genetics
KW - Esophageal Neoplasms/genetics
KW - Exome
KW - Genes, Neoplasm/genetics
KW - Genetic Heterogeneity
KW - Humans
KW - Immune Evasion
KW - Immunotherapy
KW - Mismatch Repair Endonuclease PMS2/genetics
KW - MutL Protein Homolog 1/genetics
KW - MutS Homolog 2 Protein/genetics
KW - Mutation
KW - Phenotype
KW - Phylogeny
KW - Stomach Neoplasms/genetics
U2 - 10.1038/s41467-019-13915-7
DO - 10.1038/s41467-019-13915-7
M3 - SCORING: Journal article
C2 - 31949146
VL - 11
SP - 139
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -