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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, Jahrgang 11, Nr. 1, 16.01.2020, S. 139.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

von Loga, K, Woolston, A, Punta, M, Barber, LJ, Griffiths, B, Semiannikova, M, Spain, G, Challoner, B, Fenwick, K, Simon, R, Marx, A, Sauter, G, Lise, S, Matthews, N & Gerlinger, M 2020, 'Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer', NAT COMMUN, Jg. 11, Nr. 1, S. 139. https://doi.org/10.1038/s41467-019-13915-7

APA

von Loga, K., Woolston, A., Punta, M., Barber, L. J., Griffiths, B., Semiannikova, M., Spain, G., Challoner, B., Fenwick, K., Simon, R., Marx, A., Sauter, G., Lise, S., Matthews, N., & Gerlinger, M. (2020). Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. NAT COMMUN, 11(1), 139. https://doi.org/10.1038/s41467-019-13915-7

Vancouver

von Loga K, Woolston A, Punta M, Barber LJ, Griffiths B, Semiannikova M et al. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. NAT COMMUN. 2020 Jan 16;11(1):139. https://doi.org/10.1038/s41467-019-13915-7

Bibtex

@article{c64dd6ca2b8448369331732526589823,
title = "Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer",
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.",
keywords = "Adenocarcinoma/genetics, DNA Mismatch Repair, DNA-Binding Proteins/genetics, Esophageal Neoplasms/genetics, Exome, Genes, Neoplasm/genetics, Genetic Heterogeneity, Humans, Immune Evasion, Immunotherapy, Mismatch Repair Endonuclease PMS2/genetics, MutL Protein Homolog 1/genetics, MutS Homolog 2 Protein/genetics, Mutation, Phenotype, Phylogeny, Stomach Neoplasms/genetics",
author = "{von Loga}, Katharina and Andrew Woolston and Marco Punta and Barber, {Louise J} and Beatrice Griffiths and Maria Semiannikova and Georgia Spain and Benjamin Challoner and Kerry Fenwick and Ronald Simon and Andreas Marx and Guido Sauter and Stefano Lise and Nik Matthews and Marco Gerlinger",
year = "2020",
month = jan,
day = "16",
doi = "10.1038/s41467-019-13915-7",
language = "English",
volume = "11",
pages = "139",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

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 -