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- Title
Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy.
- Authors
Brosda, Sandra; Aoude, Lauren G.; Bonazzi, Vanessa F.; Patel, Kalpana; Lonie, James M.; Belle, Clemence J.; Newell, Felicity; Koufariotis, Lambros T.; Addala, Venkateswar; Naeini, Marjan M.; AGITG DOCTOR Investigators; Simes, John; Walpole, Euan T.; Mai, Gang T.; Watson, David I.; Karapetis, Chris S.; Gebski, Val; Barnes, Elizabeth H.; Oostendorp, Martijn; Wilson, Kate
- 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.
- Publication
Genome Medicine, 2024, Vol 16, Issue 1, p1
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/s13073-024-01362-z