Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy.
Genetics
Oesophageal adenocarcinoma
Treatment impact
Tumour evolution
Whole-genome sequencing
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
17 Jul 2024
17 Jul 2024
Historique:
received:
12
12
2023
accepted:
09
07
2024
medline:
18
7
2024
pubmed:
18
7
2024
entrez:
17
7
2024
Statut:
epublish
Résumé
Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance. Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define 'shared' (between both samples) and 'private' (present in one sample) mutations. Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones. This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.
Sections du résumé
BACKGROUND
BACKGROUND
Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.
METHODS
METHODS
Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define 'shared' (between both samples) and 'private' (present in one sample) mutations.
RESULTS
RESULTS
Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones.
CONCLUSIONS
CONCLUSIONS
This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.
Identifiants
pubmed: 39020404
doi: 10.1186/s13073-024-01362-z
pii: 10.1186/s13073-024-01362-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
90Subventions
Organisme : Cancer Australia
ID : APP2010313
Organisme : Cancer Australia
ID : APP2012395
Organisme : Metro South Health Research Support Scheme
ID : RSS_2022_039
Organisme : Cure Cancer Australia Foundation
ID : CCAF2023-Aoude
Organisme : National Health and Medical Research Council
ID : APP1139071
Organisme : National Health and Medical Research Council
ID : APP2018244
Organisme : Royal Australasian College of Surgeons
ID : Mitchell Crouch Fellowship
Organisme : PA Research Foundation
ID : RSS_2020_040
Organisme : The University of Queensland
ID : Philip Walker Surgery Research Scholarship
Investigateurs
John Simes
(J)
Euan T Walpole
(ET)
Gang T Mai
(GT)
David I Watson
(DI)
Chris S Karapetis
(CS)
Val Gebski
(V)
Elizabeth H Barnes
(EH)
Martijn Oostendorp
(M)
Kate Wilson
(K)
Stephen P Ackland
(SP)
Jenny Shannon
(J)
Gavin Marx
(G)
Matthew Burge
(M)
Robert Finch
(R)
Janine Thomas
(J)
Suresh Varma
(S)
Louise Nott
(L)
Informations de copyright
© 2024. The Author(s).
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