Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy
-
Published:2024-07-17
Issue:1
Volume:16
Page:
-
ISSN:1756-994X
-
Container-title:Genome Medicine
-
language:en
-
Short-container-title:Genome Med
Author:
Brosda SandraORCID, Aoude Lauren G., Bonazzi Vanessa F., Patel Kalpana, Lonie James M., Belle Clemence J., Newell Felicity, Koufariotis Lambros T., Addala Venkateswar, Naeini Marjan M., Simes John, Walpole Euan T., Mai Gang T., Watson David I., Karapetis Chris S., Gebski Val, Barnes Elizabeth H., Oostendorp Martijn, Wilson Kate, Ackland Stephen P., Shannon Jenny, Marx Gavin, Burge Matthew, Finch Robert, Thomas Janine, Varma Suresh, Nott Louise, Pearson John V., Krause Lutz, Waddell Nicola, Barbour Andrew P.,
Abstract
Abstract
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
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
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
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.
Funder
Cancer Australia Metro South Health Research Support Scheme Cure Cancer Australia Foundation National Health and Medical Research Council Royal Australasian College of Surgeons PA Research Foundation The University of Queensland
Publisher
Springer Science and Business Media LLC
Reference69 articles.
1. Swisher SG, Winter KA, Komaki RU, Ajani JA, Wu TT, Hofstetter WL, et al. A phase II study of a paclitaxel-based chemoradiation regimen with selective surgical salvage for resectable locoregionally advanced esophageal cancer: initial reporting of RTOG 0246. Int J Radiat Oncol Biol Phys. 2012;82(5):1967–72. 2. Lordick F, Mariette C, Haustermans K, Obermannova R, Arnold D, Committee EG. Oesophageal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v50–7. 3. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759–71. 4. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191–203. 5. Secrier M, Li X, de Silva N, Eldridge MD, Contino G, Bornschein J, et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet. 2016;48(10):1131–41.
|
|