Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy

Genome Med. 2024 Jul 17;16(1):90. doi: 10.1186/s13073-024-01362-z.

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.

Keywords: Genetics; Oesophageal adenocarcinoma; Treatment impact; Tumour evolution; Whole-genome sequencing.

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / therapy
  • Aged
  • Esophageal Neoplasms* / drug therapy
  • Esophageal Neoplasms* / genetics
  • Esophageal Neoplasms* / therapy
  • Evolution, Molecular
  • Female
  • Genetic Heterogeneity
  • Genomics / methods
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Prognosis
  • Whole Genome Sequencing

Supplementary concepts

  • Adenocarcinoma Of Esophagus